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http://www.ncbi.nlm.nih.gov/pubmed/16443930 | 1. Bioinformatics. 2006 Apr 15;22(8):1027-8. doi: 10.1093/bioinformatics/btl026.
Epub 2006 Jan 28.
siRecords: an extensive database of mammalian siRNAs with efficacy ratings.
Ren Y(1), Gong W, Xu Q, Zheng X, Lin D, Wang Y, Li T.
Author information:
(1)Department of Neuroscience, University of Minnesota Minneapolis, MN 55455,
USA.
Short interfering RNAs (siRNAs) have been gaining popularity as the gene
knock-down tool of choice by many researchers because of the clean nature of
their workings as well as the technical simplicity and cost efficiency in their
applications. We have constructed siRecords, a database of siRNAs experimentally
tested by researchers with consistent efficacy ratings. This database will help
siRNA researchers develop more reliable siRNA design rules; in the mean time,
siRecords will benefit experimental researchers directly by providing them with
information about the siRNAs that have been experimentally tested against the
genes of their interest. Currently, more than 4100 carefully annotated siRNA
sequences obtained from more than 1200 published siRNA studies are hosted in
siRecords. This database will continue to expand as more experimentally tested
siRNAs are published.
AVAILABILITY: The siRecords database can be accessed at
http://siRecords.umn.edu/siRecords/
DOI: 10.1093/bioinformatics/btl026
PMID: 16443930 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14961259 | 1. Mar Biotechnol (NY). 2002 Jun;4(3):256-66. doi: 10.1007/s10126-002-0017-x.
Gene knock-down in rainbow trout embryos using antisense morpholino
phosphorodiamidate oligonucleotides.
Boonanuntanasarn S(1), Yoshizaki G, Takeuchi Y, Morita T, Takeuchi T.
Author information:
(1)Laboratory of Fish Culture, Tokyo University of Fisheries, Konan, Minato,
Tokyo 108-8477, Japan.
Gene knock-down technology using antisense molecules has many applications for
studying gene function, disrupting undesirable genetic traits, as well as
providing effective therapy for a number of viral diseases. Encouraged by these
applications, we developed a gene knock-down technique to interfere with gene
expression using transgenic rainbow trout expressing the green fluorescent
protein (GFP) gene as a model. One of the antisense morpholino
phosphorodiamidate oligonucleotides (AMOs) used in this study (AtGFP-1) was 25
nucleotides in length and localized against codons 2 to 8 of GFP messenger RNA.
Microinjection of AtGFP-1 into the blastodisc of fertilized eggs decreased the
level of GFP gene expression in a dose-dependent manner, A comparison of the
effects of various doses of AtGFP-1 suggested that 10 ng of AtGFP-1 was the
optimal concentration in that it interfered with specific gene expression
without being strongly toxic to trout embryos. Conversely, morpholino
phosphorodiamidate oligonucleotides with the inverted AtGFP-1 sequence, which
cannot bind to the target mRNA, did not inhibit GFP gene expression. AtGFP-1 did
not affect the expression of nontargeted genes such as the skeletal muscle actin
and foreign lacZ genes. These results also indicate that AtGFP-1 interfered with
the expression of only the targeted gene. Western blot and reverse transcriptase
polymerase chain reaction analyses revealed that the amount of GFP protein
drastically decreased whereas the mRNA level was not affected by AtGFP-1,
suggesting that AtGFP-1 blocked specific gene function at the translational
level. Further, this gene inhibition persisted until the hatching stage. Another
AMO, which was localized against the junction region between the 5? untranslated
region and the starting codon of GFP mRNA (AtGFP-2), also caused inhibition
effects. Thus AMOs can have potent and specific gene knock-down effects in trout
embryos. This technology may be useful for examining the roles of selected genes
and disrupting their expression during embryonic development of salmonid fish.
DOI: 10.1007/s10126-002-0017-x
PMID: 14961259 |
http://www.ncbi.nlm.nih.gov/pubmed/18577207 | 1. BMC Mol Biol. 2008 Jun 24;9:60. doi: 10.1186/1471-2199-9-60.
Off-target effects of siRNA specific for GFP.
Tschuch C(1), Schulz A, Pscherer A, Werft W, Benner A, Hotz-Wagenblatt A,
Barrionuevo LS, Lichter P, Mertens D.
Author information:
(1)Division of Molecular Genetics, German Cancer Research Center, Heidelberg,
Germany. [email protected]
BACKGROUND: Gene knock down by RNAi is a highly effective approach to silence
gene expression in experimental as well as therapeutic settings. However, this
widely used methodology entails serious pitfalls, especially concerning
specificity of the RNAi molecules.
RESULTS: We tested the most widely used control siRNA directed against GFP for
off-target effects and found that it deregulates in addition to GFP a set of
endogenous target genes. The off-target effects were dependent on the amount of
GFP siRNA transfected and were detected in a variety of cell lines. Since the
respective siRNA molecule specific for GFP is widely used as negative control
for RNAi experiments, we studied the complete set of off-target genes of this
molecule by genome-wide expression profiling. The detected modulated mRNAs had
target sequences homologous to the siRNA as small as 8 basepairs in size.
However, we found no restriction of sequence homology to 3'UTR of target genes.
CONCLUSION: We can show that even siRNAs without a physiological target have
sequence-specific off-target effects in mammalian cells. Furthermore, our
analysis defines the off-target genes affected by the siRNA that is commonly
used as negative control and directed against GFP. Since off-target effects can
hardly be avoided, the best strategy is to identify false positives and exclude
them from the results. To this end, we provide the set of false positive genes
deregulated by the commonly used GFP siRNA as a reference resource for future
siRNA experiments.
DOI: 10.1186/1471-2199-9-60
PMCID: PMC2443166
PMID: 18577207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16509424 | 1. Harefuah. 2006 Feb;145(2):156-9, 163.
[Gene silencing RNAi technology: possible application to therapy].
[Article in Hebrew]
Vestin A(1), Weinstein J, Davidov E, Sidi Y, Yakobson EA.
Author information:
(1)Molecular Cell Biology Laboratory, Chaim Sheba Medical Center, Tel Hashomer,
Department of Internal Medicine C, Chaim Sheba Medical Center, Tel Hashomer.
[email protected]
RNA interference (RNAi), i.e. gene silencing, or gene expression down-regulation
is the process whereby a double-stranded RNA (dsRNA) induces the
homology-dependent degradation of cognate messenger RNA (mRNA). When dsRNA is
introduced into cells, an RNA-induced silencing complex (RISC) is assembled.
RISC serves as cellular machinery that is responsible for the specific mRNA
degradation. This process results in the subsequent reduction of the specific
protein translated from appropriate mRNA. Short RNA duplexes (21 nucleotide),
called small interfering RNA (siRNA), have become the major tool for induction
of gene silencing. With the human genome mapped and sequenced, attempts are
currently being made to manipulate the expression of genes involved in viral
diseases, carcinogenesis and other disorders with the aim of developing novel
therapies.
PMID: 16509424 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33923658 | 1. Cells. 2021 Apr 16;10(4):923. doi: 10.3390/cells10040923.
Regulation of RNA Splicing: Aberrant Splicing Regulation and Therapeutic Targets
in Cancer.
Kitamura K(1)(2), Nimura K(1).
Author information:
(1)Division of Gene Therapy Science, Department of Genome Biology, Graduate
School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871,
Japan.
(2)Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of
Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA)
by removing introns and exons. The combination of inclusion and exclusion of
introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a
limited number of genes. Cancer cells acquire cancer-specific mechanisms through
aberrant splicing regulation to acquire resistance to treatment and to promote
malignancy. Splicing regulation involves many factors, such as proteins,
non-coding RNAs, and DNA sequences at many steps. Thus, the dysregulation of
splicing is caused by many factors, including mutations in RNA splicing factors,
aberrant expression levels of RNA splicing factors, small nuclear
ribonucleoproteins biogenesis, mutations in snRNA, or genomic sequences that are
involved in the regulation of splicing, such as 5' and 3' splice sites, branch
point site, splicing enhancer/silencer, and changes in the chromatin status that
affect the splicing profile. This review focuses on the dysregulation of RNA
splicing related to cancer and the associated therapeutic methods.
DOI: 10.3390/cells10040923
PMCID: PMC8073995
PMID: 33923658 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/24617759 | 1. Biochemistry. 2014 Apr 1;53(12):1882-98. doi: 10.1021/bi401715v. Epub 2014 Mar
20.
Structure and function of pre-mRNA 5'-end capping quality control and 3'-end
processing.
Jurado AR(1), Tan D, Jiao X, Kiledjian M, Tong L.
Author information:
(1)Department of Biological Sciences, Columbia University , New York, New York
10027, United States.
Messenger RNA precursors (pre-mRNAs) are produced as the nascent transcripts of
RNA polymerase II (Pol II) in eukaryotes and must undergo extensive maturational
processing, including 5'-end capping, splicing, and 3'-end cleavage and
polyadenylation. This review will summarize the structural and functional
information reported over the past few years on the large machinery required for
the 3'-end processing of most pre-mRNAs, as well as the distinct machinery for
the 3'-end processing of replication-dependent histone pre-mRNAs, which have
provided great insights into the proteins and their subcomplexes in these
machineries. Structural and biochemical studies have also led to the
identification of a new class of enzymes (the DXO family enzymes) with activity
toward intermediates of the 5'-end capping pathway. Functional studies
demonstrate that these enzymes are part of a novel quality surveillance
mechanism for pre-mRNA 5'-end capping. Incompletely capped pre-mRNAs are
produced in yeast and human cells, in contrast to the general belief in the
field that capping always proceeds to completion, and incomplete capping leads
to defects in splicing and 3'-end cleavage in human cells. The DXO family
enzymes are required for the detection and degradation of these defective RNAs.
DOI: 10.1021/bi401715v
PMCID: PMC3977584
PMID: 24617759 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25487206 | 1. Methods Mol Biol. 2015;1255:79-89. doi: 10.1007/978-1-4939-2175-1_8.
In vitro analysis of cleavage and polyadenylation in Arabidopsis.
Zhao H(1), Li QQ.
Author information:
(1)Department of Plant Pathology, College of Plant Protection, Nanjing
Agricultural University, Nanjing, 210095, China, [email protected].
In eukaryotes, pre-messenger RNA (pre-mRNA) cleavage and polyadenylation is one
of the necessary processing steps that produce a mature and functional mRNA.
Regulation on pre-mRNA cleavage and polyadenylation affects other processes such
as mRNA translocation, stability, and translation. The process of pre-mRNA
cleavage and polyadenylation, and its relationship with RNA splicing and
translation, have been extensively studied due to its importance in vivo. A
successful in vitro system has provided enormous amount of information to the
study of cleavage and polyadenylation in the mammalian and yeast systems. Here,
we describe an in vitro pre-mRNA cleavage system that faithfully cleaves
pre-mRNA substrate using Arabidopsis cell/tissue cultures.
DOI: 10.1007/978-1-4939-2175-1_8
PMID: 25487206 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19429779 | 1. Eukaryot Cell. 2009 Jul;8(7):990-1000. doi: 10.1128/EC.00075-09. Epub 2009 May
8.
Spliceosomal proteomics in Trypanosoma brucei reveal new RNA splicing factors.
Luz Ambrósio D(1), Lee JH, Panigrahi AK, Nguyen TN, Cicarelli RM, Günzl A.
Author information:
(1)Department of Genetics and Developmental Biology, University of Connecticut
Health Center, Farmington, Connecticut 06030-3301, USA.
In trypanosomatid parasites, spliced leader (SL) trans splicing is an essential
nuclear mRNA maturation step which caps mRNAs posttranscriptionally and, in
conjunction with polyadenylation, resolves individual mRNAs from polycistronic
precursors. While all trypanosomatid mRNAs are trans spliced, intron removal by
cis splicing is extremely rare and predicted to occur in only four pre-mRNAs.
trans- and cis-splicing reactions are carried out by the spliceosome, which
consists of U-rich small nuclear ribonucleoprotein particles (U snRNPs) and of
non-snRNP factors. Mammalian and yeast spliceosome complexes are well
characterized and found to be associated with up to 170 proteins. Despite the
central importance of trans splicing in trypanosomatid gene expression, only the
core RNP proteins and a few snRNP-specific proteins are known. To characterize
the trypanosome spliceosomal protein repertoire, we conducted a proteomic
analysis by tagging and tandem affinity-purifying the canonical core RNP protein
SmD1 in Trypanosoma brucei and by identifying copurified proteins by mass
spectrometry. The set of 47 identified proteins harbored nearly all spliceosomal
snRNP factors characterized in trypanosomes thus far and 21 proteins lacking a
specific annotation. A bioinformatic analysis combined with protein pull-down
assays and immunofluorescence microscopy identified 10 divergent orthologues of
known splicing factors, including the missing U1-specific protein U1A. In
addition, a novel U5-specific, and, as we show, an essential splicing factor was
identified that shares a short, highly conserved N-terminal domain with the
yeast protein Cwc21p and was thus tentatively named U5-Cwc21. Together, these
data strongly indicate that most of the identified proteins are components of
the spliceosome.
DOI: 10.1128/EC.00075-09
PMCID: PMC2708463
PMID: 19429779 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31132066 | 1. J Vis Exp. 2019 May 13;(147). doi: 10.3791/59497.
Artificial RNA Polymerase II Elongation Complexes for Dissecting
Co-transcriptional RNA Processing Events.
Noe Gonzalez M(1), Conaway JW(2), Conaway RC(3).
Author information:
(1)Stowers Institute for Medical Research.
(2)Stowers Institute for Medical Research; Department of Biochemistry and
Molecular Biology, Kansas University Medical Center.
(3)Stowers Institute for Medical Research; Department of Biochemistry and
Molecular Biology, Kansas University Medical Center; [email protected].
Eukaryotic mRNA synthesis is a complex biochemical process requiring
transcription of a DNA template into a precursor RNA by the multi-subunit enzyme
RNA polymerase II and co-transcriptional capping and splicing of the precursor
RNA to form the mature mRNA. During mRNA synthesis, the RNA polymerase II
elongation complex is a target for regulation by a large collection of
transcription factors that control its catalytic activity, as well as the
capping, splicing, and 3'-processing enzymes that create the mature mRNA.
Because of the inherent complexity of mRNA synthesis, simpler experimental
systems enabling isolation and investigation of its various co-transcriptional
stages have great utility. In this article, we describe one such simple
experimental system suitable for investigating co-transcriptional RNA capping.
This system relies on defined RNA polymerase II elongation complexes assembled
from purified polymerase and artificial transcription bubbles. When immobilized
via biotinylated DNA, these RNA polymerase II elongation complexes provide an
easily manipulable tool for dissecting co-transcriptional RNA capping and
mechanisms by which the elongation complex recruits and regulates capping enzyme
during co-transcriptional RNA capping. We anticipate this system could be
adapted for studying recruitment and/or assembly of proteins or protein
complexes with roles in other stages of mRNA maturation coupled to the RNA
polymerase II elongation complex.
DOI: 10.3791/59497
PMID: 31132066 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25836925 | 1. Genes (Basel). 2015 Mar 31;6(2):163-84. doi: 10.3390/genes6020163.
Nuclear export of messenger RNA.
Katahira J(1)(2).
Author information:
(1)Biomolecular Networks Laboratories, Graduate School of Frontier Biosciences,
Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
[email protected].
(2)Department of Biochemistry, Graduate School of Medicine, Osaka University,
2-2 Yamadaoka, Suita, Osaka 565-0871, Japan . [email protected].
Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an
essential step of eukaryotic gene expression. In the cell nucleus, a precursor
mRNA undergoes a series of processing steps, including capping at the 5' ends,
splicing and cleavage/polyadenylation at the 3' ends. During this process, the
mRNA associates with a wide variety of proteins, forming a messenger
ribonucleoprotein (mRNP) particle. Association with factors involved in nuclear
export also occurs during transcription and processing, and thus nuclear export
is fully integrated into mRNA maturation. The coupling between mRNA maturation
and nuclear export is an important mechanism for providing only fully functional
and competent mRNA to the cytoplasmic translational machinery, thereby ensuring
accuracy and swiftness of gene expression. This review describes the molecular
mechanism of nuclear mRNA export mediated by the principal transport factors,
including Tap-p15 and the TREX complex.
DOI: 10.3390/genes6020163
PMCID: PMC4488659
PMID: 25836925 |
http://www.ncbi.nlm.nih.gov/pubmed/35930970 | 1. Curr Opin Struct Biol. 2022 Aug;75:102431. doi: 10.1016/j.sbi.2022.102431.
Epub 2022 Aug 2.
Structural basis of mRNA maturation: Time to put it together.
Vorländer MK(1), Pacheco-Fiallos B(2), Plaschka C(3).
Author information:
(1)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC),
Campus-Vienna-Biocenter 1, 1030, Vienna, Austria. Electronic address:
https://twitter.com/@MVorlandr.
(2)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC),
Campus-Vienna-Biocenter 1, 1030, Vienna, Austria; Vienna BioCenter PhD Program,
Doctoral School of the University of Vienna and Medical University of Vienna,
1030, Vienna, Austria. Electronic address: https://twitter.com/@bpachecofiallos.
(3)Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC),
Campus-Vienna-Biocenter 1, 1030, Vienna, Austria. Electronic address:
[email protected].
In eukaryotes, the expression of genetic information begins in the cell nucleus
with precursor messenger RNA (pre-mRNA) transcription and processing into mature
mRNA. The mRNA is subsequently recognized and packaged by proteins into an mRNA
ribonucleoprotein complex (mRNP) and exported to the cytoplasm for translation.
Each of the nuclear mRNA maturation steps is carried out by a dedicated
molecular machine. Here, we highlight recent structural and mechanistic insights
into how these machines function, including the capping enzyme, the spliceosome,
the 3'-end processing machinery, and the transcription-export complex. While we
increasingly understand individual steps of nuclear gene expression, many
questions remain. For example, we are only beginning to reveal how mature mRNAs
are recognized and packaged for nuclear export and how mRNA maturation events
are coupled to transcription and to each other. Advances in the preparation of
recombinant and endogenous protein-nucleic acid complexes, cryo-electron
microscopy, and machine learning promise exciting insights into the mechanisms
of nuclear gene expression and its spatial organization.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.sbi.2022.102431
PMID: 35930970 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/21823231 | 1. Wiley Interdiscip Rev RNA. 2011 Sep-Oct;2(5):718-31. doi: 10.1002/wrna.87.
Epub 2011 Apr 25.
Biogenesis of spliceosomal small nuclear ribonucleoproteins.
Fischer U(1), Englbrecht C, Chari A.
Author information:
(1)Department of Biochemistry, University of Wuerzburg, Germany.
[email protected]
Virtually, all eukaryotic mRNAs are synthesized as precursor molecules that need
to be extensively processed in order to serve as a blueprint for proteins. The
three most prevalent processing steps are the capping reaction at the 5'-end,
the removal of intervening sequences by splicing, and the formation of poly
(A)-tails at the 3'-end of the message by polyadenylation. A large number of
proteins and small nuclear ribonucleoprotein complexes (snRNPs) interact with
the mRNA and enable the different maturation steps. This chapter focuses on the
biogenesis of snRNPs, the major components of the pre-mRNA splicing machinery
(spliceosome). A large body of evidence has revealed an intricate and segmented
pathway for the formation of snRNPs that involves nucleo-cytoplasmic transport
events and elaborates assembly strategies. We summarize the knowledge about the
different steps with an emphasis on trans-acting factors of snRNP maturation of
higher eukaryotes. WIREs RNA 2011 2 718-731 DOI: 10.1002/wrna.87 For further
resources related to this article, please visit the WIREs website.
Copyright © 2011 John Wiley & Sons, Ltd.
DOI: 10.1002/wrna.87
PMID: 21823231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25761502 | 1. J Nutr. 2015 May;145(5):841-6. doi: 10.3945/jn.114.203216. Epub 2015 Mar 11.
Role of precursor mRNA splicing in nutrient-induced alterations in gene
expression and metabolism.
Ravi S(1), Schilder RJ(2), Kimball SR(3).
Author information:
(1)Department of Cellular and Molecular Physiology, The Pennsylvania State
University College of Medicine, Hershey, PA; and.
(2)Departments of Entomology and Biology, The Pennsylvania State University,
State College, PA.
(3)Department of Cellular and Molecular Physiology, The Pennsylvania State
University College of Medicine, Hershey, PA; and [email protected].
Precursor mRNA (pre-mRNA) splicing is a critical step in gene expression that
results in the removal of intronic sequences from immature mRNA, leading to the
production of mature mRNA that can be translated into protein. Alternative
pre-mRNA splicing is the process whereby alternative exons and/or introns are
selectively included or excluded, generating mature mRNAs that encode proteins
that may differ in function. The resulting alterations in the pattern of protein
isoform expression can result in changes in protein-protein interaction,
subcellular localization, and flux through metabolic pathways. Although basic
mechanisms of pre-mRNA splicing of introns and exons are reasonably well
characterized, how these mechanisms are regulated remains poorly understood. The
goal of this review is to highlight selected recent advances in our
understanding of the regulation of pre-mRNA splicing by nutrients and modulation
of nutrient metabolism that result from changes in pre-mRNA splicing.
© 2015 American Society for Nutrition.
DOI: 10.3945/jn.114.203216
PMCID: PMC4408736
PMID: 25761502 [Indexed for MEDLINE]
Conflict of interest statement: Author disclosures: S Ravi, RJ Schilder, and SR
Kimball, no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27350684 | 1. J Genet. 2016 Jun;95(2):389-97. doi: 10.1007/s12041-016-0652-z.
Mutant allele of rna14 in fission yeast affects pre-mRNA splicing.
Yadav S(1), Sonkar A, Ahamad N, Ahmed S.
Author information:
(1)Molecular and Structural Biology Division, CSIR-Central Drug Research
Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226 031,
[email protected].
Spliceosome and 3'-end processing complexes are necessary for the precursor mRNA
(pre-mRNA) maturation. Spliceosome complex removes noncoding introns, while
3'-end processing involves in cleavage and addition of poly(A) tails to the
nascent transcript. Rna14 protein in budding yeast has been implicated in
cleavage and polyadenylation of mRNA in the nucleus but their role in the
pre-mRNA splicing has not been studied. Here, we report the isolation of a
mutant allele of rna14 in fission yeast, Schizosaccharomyces pombe that exhibits
reduction in protein level of Chk1 at the nonpermissive temperature, primarily
due to the defects in posttranscriptional processing. Reverse
transcriptase-polymerase chain reaction analysis reveals defective splicing of
the chk1(+) transcript at the nonpermissive temperature. Apart from chk1(+), the
splicing of some other genes were also found to be defective at the
nonpermissive temperature suggesting that Rna14 might be involved in pre-mRNA
splicing. Subsequently, genetic interaction of Rna14 with prp1 and physical
interactions with Prp28 suggest that the Rna14 might be part of a larger protein
complex responsible for the pre-mRNA maturation.
DOI: 10.1007/s12041-016-0652-z
PMID: 27350684 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12091875 | 1. Nat Struct Biol. 2002 Aug;9(8):576-81. doi: 10.1038/nsb822.
Early organization of pre-mRNA during spliceosome assembly.
Kent OA(1), MacMillan AM.
Author information:
(1)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada.
Intron excision from precursor mRNAs (pre-mRNAs) in eukaryotes requires
juxtaposition of reactive functionalities within the substrate at the heart of
the spliceosome where the two chemical steps of splicing occur. Although a
series of interactions between pre-mRNAs, pre-spliceosomal and spliceosomal
factors is well established, the molecular mechanisms of splicing machinery
assembly, as well as the temporal basis for organization of the substrate for
splicing, remain poorly understood. Here we have used a directed hydroxyl
radical probe tethered to pre-mRNA substrates to map the structure of the
pre-mRNA substrate during the spliceosome assembly process. These studies
indicate an early organization and proximation of conserved pre-mRNA sequences
during spliceosome assembly/recruitment and suggest a mechanism for the
formation of the final active site of the mature spliceosome.
DOI: 10.1038/nsb822
PMID: 12091875 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6744418 | 1. Cell. 1984 Jul;37(3):993-9. doi: 10.1016/0092-8674(84)90433-1.
Requirement of a downstream sequence for generation of a poly(A) addition site.
McDevitt MA, Imperiale MJ, Ali H, Nevins JR.
The 3' terminus of most, if not all, eucaryotic polyadenylated mRNAs is formed
as a result of endonucleolytic cleavage of a larger precursor RNA. That is,
transcription does not terminate at the mRNA 3' sequence but rather proceeds
through this site, terminating at some distance downstream. Using a plasmid
containing the adenovirus E2A transcriptional unit, we have investigated the
sequence requirement for the formation of a mature mRNA 3' terminus, focusing on
the role of sequences immediately distal to the poly(A) addition site. Deletion
mutants were constructed in the region distal to the poly(A) addition site and
assayed by transfection into human 293 cells. The results demonstrate that 35
nucleotides distal to the site of poly(A) addition are sufficient for the
formation of a mature E2 mRNA. However, removal of an additional 15 nucleotides,
leaving 20 nucleotides distal to the poly(A) site, abolished the ability to
produce functional E2A mRNA. The defect in the production of functional mRNA
from such a mutant appears to be in the proper cleavage of the primary
transcript at the poly(A) addition site. It would thus appear that sequences
immediately distal to the site of poly(A) addition do not contribute to the
mature mRNA but are essential for the formation of mature mRNA.
DOI: 10.1016/0092-8674(84)90433-1
PMID: 6744418 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14576302 | 1. Nucleic Acids Res. 2003 Nov 1;31(21):6157-67. doi: 10.1093/nar/gkg824.
Inhibition of pre-mRNA splicing by synthetic branched nucleic acids.
Carriero S(1), Damha MJ.
Author information:
(1)Department of Chemistry, Otto Maass Chemistry Building, McGill University,
801 Sherbrooke St West, Montreal, QC, H3A 2K6, Canada.
The cellular transformation of a precursor mRNA (pre-mRNA) into its mature or
functional form proceeds by way of a splicing reaction, in which the exons are
ligated to form the mature linear RNA and the introns are excised as branched or
lariat RNAs. We have prepared a series of branched compounds (bRNA and bDNA),
and studied the effects of such molecules on the efficiency of mammalian
pre-mRNA splicing in vitro. Y-shaped RNAs containing an unnatural
L-2'-deoxycytidine unit (L-dC) at the 3' termini are highly stabilized against
exonuclease hydrolysis in HeLa nuclear extracts, and are potent inhibitors of
the splicing pathway. A bRNA containing internal 2'-O-methyl ribopyrimidine
units and L-dC at the 3' ends was at least twice as potent as the most potent of
the bRNAs containing no 2' modifications, with an IC50 of approximately 5 micro
M. Inhibitory activity was maintained in a branched molecule containing an
arabino-adenosine branchpoint which, unlike the native bRNAs, resisted cleavage
by the lariat- debranching enzyme. The data obtained suggest that binding and
sequestering of a branch recognition factor by the branched nucleic acids is an
early event, which occurs prior to the first chemical step of splicing.
Probably, an early recognition element preferentially binds to the synthetic
branched molecules over the native pre-mRNA. As such, synthetic bRNAs may prove
to be invaluable tools for the purification and identification of the putative
branchpoint recognition factor.
DOI: 10.1093/nar/gkg824
PMCID: PMC275466
PMID: 14576302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17210931 | 1. Genome Res. 2007 Feb;17(2):156-65. doi: 10.1101/gr.5532707. Epub 2007 Jan 8.
Widespread mRNA polyadenylation events in introns indicate dynamic interplay
between polyadenylation and splicing.
Tian B(1), Pan Z, Lee JY.
Author information:
(1)Department of Biochemistry and Molecular Biology, New Jersey Medical School,
University of Medicine and Dentistry of New Jersey, Newark, NJ 07101, USA.
[email protected]
mRNA polyadenylation and pre-mRNA splicing are two essential steps for the
maturation of most human mRNAs. Studies have shown that some genes generate mRNA
variants involving both alternative polyadenylation and alternative splicing.
Polyadenylation in introns can lead to conversion of an internal exon to a 3'
terminal exon, which is termed composite terminal exon, or usage of a 3'
terminal exon that is otherwise skipped, which is termed skipped terminal exon.
Using cDNA/EST and genome sequences, we identified polyadenylation sites in
introns for all currently known human genes. We found that approximately 20%
human genes have at least one intronic polyadenylation event that can
potentially lead to mRNA variants, most of which encode different protein
products. The conservation of human intronic poly(A) sites in mouse and rat
genomes is lower than that of poly(A) sites in 3'-most exons. Quantitative
analysis of a number of mRNA variants generated by intronic poly(A) sites
suggests that the intronic polyadenylation activity can vary under different
cellular conditions for most genes. Furthermore, we found that weak 5' splice
site and large intron size are the determining factors controlling the usage of
composite terminal exon poly(A) sites, whereas skipped terminal exon poly(A)
sites tend to be associated with strong polyadenylation signals. Thus, our data
indicate that dynamic interplay between polyadenylation and splicing leads to
widespread polyadenylation in introns and contributes to the complexity of
transcriptome in the cell.
DOI: 10.1101/gr.5532707
PMCID: PMC1781347
PMID: 17210931 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34016162 | 1. Transl Neurodegener. 2021 May 20;10(1):16. doi: 10.1186/s40035-021-00240-7.
Neurodegenerative diseases: a hotbed for splicing defects and the potential
therapies.
Li D(#)(1)(2), McIntosh CS(#)(1)(2), Mastaglia FL(1)(2), Wilton SD(1)(2),
Aung-Htut MT(3)(4).
Author information:
(1)Centre for Molecular Medicine and Innovative Therapeutics, Health Futures
Institute, Murdoch University, Perth, Western Australia, Australia.
(2)Perron Institute for Neurological and Translational Science, Centre for
Neuromuscular and Neurological Disorders, The University of Western Australia,
Perth, Western Australia, Australia.
(3)Centre for Molecular Medicine and Innovative Therapeutics, Health Futures
Institute, Murdoch University, Perth, Western Australia, Australia.
[email protected].
(4)Perron Institute for Neurological and Translational Science, Centre for
Neuromuscular and Neurological Disorders, The University of Western Australia,
Perth, Western Australia, Australia. [email protected].
(#)Contributed equally
Erratum in
Transl Neurodegener. 2021 Oct 25;10(1):41. doi: 10.1186/s40035-021-00267-w.
Precursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic
gene expression that systematically removes non-coding regions (introns) and
ligates coding regions (exons) into a continuous message (mature mRNA). This
process is highly regulated and can be highly flexible through a process known
as alternative splicing, which allows for several transcripts to arise from a
single gene, thereby greatly increasing genetic plasticity and the diversity of
proteome. Alternative splicing is particularly prevalent in neuronal cells,
where the splicing patterns are continuously changing to maintain cellular
homeostasis and promote neurogenesis, migration and synaptic function. The
continuous changes in splicing patterns and a high demand on many cis- and
trans-splicing factors contribute to the susceptibility of neuronal tissues to
splicing defects. The resultant neurodegenerative diseases are a large group of
disorders defined by a gradual loss of neurons and a progressive impairment in
neuronal function. Several of the most common neurodegenerative diseases involve
some form of splicing defect(s), such as Alzheimer's disease, Parkinson's
disease and spinal muscular atrophy. Our growing understanding of RNA splicing
has led to the explosion of research in the field of splice-switching antisense
oligonucleotide therapeutics. Here we review our current understanding of the
effects alternative splicing has on neuronal differentiation, neuronal
migration, synaptic maturation and regulation, as well as the impact on
neurodegenerative diseases. We will also review the current landscape of
splice-switching antisense oligonucleotides as a therapeutic strategy for a
number of common neurodegenerative disorders.
DOI: 10.1186/s40035-021-00240-7
PMCID: PMC8136212
PMID: 34016162 [Indexed for MEDLINE]
Conflict of interest statement: SDW is a consultant to Sarepta Therapeutics. He
is named as an inventor on patents licensed through the University of Western
Australia to Sarepta Therapeutics, and as such is entitled to milestone and
royalty payments. DHL, CSM and MATH salaries are partly funded by Sarepta
Therapeutics. |
http://www.ncbi.nlm.nih.gov/pubmed/25081038 | 1. Mol Cells. 2014 Sep;37(9):644-9. doi: 10.14348/molcells.2014.0177. Epub 2014
Aug 1.
New links between mRNA polyadenylation and diverse nuclear pathways.
Di Giammartino DC(1), Manley JL(1).
Author information:
(1)Columbia University, Department of Biological Sciences, New York NY, 10027,
USA.
The 3' ends of most eukaryotic messenger RNAs must undergo a maturation step
that includes an endonuc-leolytic cleavage followed by addition of a
polyadenylate tail. While this reaction is catalyzed by the action of only two
enzymes it is supported by an unexpectedly large number of proteins. This
complexity reflects the necessity of coordinating this process with other
nuclear events, and growing evidence indicates that even more factors than
previously thought are necessary to connect 3' processing to additional cellular
pathways. In this review we summarize the current understanding of the molecular
machinery involved in this step of mRNA maturation, focusing on new core and
auxiliary proteins that connect polyadenylation to splicing, DNA damage,
transcription and cancer.
DOI: 10.14348/molcells.2014.0177
PMCID: PMC4179132
PMID: 25081038 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25110027 | 1. Biochem Soc Trans. 2014 Aug;42(4):1211-8. doi: 10.1042/BST20140105.
Single-molecule fluorescence-based studies on the dynamics, assembly and
catalytic mechanism of the spliceosome.
Warnasooriya C(1), Rueda D(1).
Author information:
(1)*Department of Medicine, Section of Virology and Single Molecule Imaging
Group, MRC Clinical Centre, Imperial College London, London W12 0NN, U.K.
Pre-mRNA (precursor mRNA) splicing is a key step in cellular gene expression
where introns are excised and exons are ligated together to produce mature mRNA.
This process is catalysed by the spliceosome, which consists of five snRNPs
(small nuclear ribonucleoprotein particles) and numerous protein factors.
Assembly of these snRNPs and associated proteins is a highly dynamic process,
making it challenging to study the conformational rearrangements and spliceosome
assembly kinetics in bulk studies. In the present review, we discuss recent
studies utilizing techniques based on single-molecule detection that have helped
overcome this challenge. These studies focus on the assembly dynamics and
splicing kinetics in real-time, which help understanding of spliceosomal
assembly and catalysis.
DOI: 10.1042/BST20140105
PMID: 25110027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27198613 | 1. Wiley Interdiscip Rev RNA. 2016 Sep;7(5):683-701. doi: 10.1002/wrna.1358. Epub
2016 May 20.
Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with
single-molecule fluorescence microscopy.
DeHaven AC(1)(2), Norden IS(1)(2), Hoskins AA(2).
Author information:
(1)Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison,
WI, USA.
(2)Department of Biochemistry, University of Wisconsin-Madison, Madison, WI,
USA.
The process of removing intronic sequences from a precursor to messenger RNA
(pre-mRNA) to yield a mature mRNA transcript via splicing is an integral step in
eukaryotic gene expression. Splicing is carried out by a cellular nanomachine
called the spliceosome that is composed of RNA components and dozens of
proteins. Despite decades of study, many fundamentals of spliceosome function
have remained elusive. Recent developments in single-molecule fluorescence
microscopy have afforded new tools to better probe the spliceosome and the
complex, dynamic process of splicing by direct observation of single molecules.
These cutting-edge technologies enable investigators to monitor the dynamics of
specific splicing components, whole spliceosomes, and even cotranscriptional
splicing within living cells. WIREs RNA 2016, 7:683-701. doi: 10.1002/wrna.1358
For further resources related to this article, please visit the WIREs website.
© 2016 Wiley Periodicals, Inc.
DOI: 10.1002/wrna.1358
PMCID: PMC4990488
PMID: 27198613 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18630752 | 1. Curr Top Microbiol Immunol. 2008;326:151-77. doi: 10.1007/978-3-540-76776-3_9.
Messenger RNA 3' end formation in plants.
Hunt AG(1).
Author information:
(1)Department of Plant and Soil Sciences, University of Kentucky, Lexington, KY
40546-0312, USA. [email protected]
Messenger RNA 3' end formation is an integral step in the process that gives
rise to mature, translated messenger RNAs in eukaryotes. With this step, a
pre-messenger RNA is processed and polyadenylated, giving rise to a mature mRNA
bearing the characteristic poly(A) tract. The poly(A) tract is a fundamental
feature of mRNAs, participating in the process of translation initiation and
being the focus of control mechanisms that define the lifetime of mRNAs. Thus
messenger RNA 3' end formation impacts two steps in mRNA biogenesis and
function. Moreover, mRNA 3' end formation is something of a bridge that
integrates numerous other steps in mRNA biogenesis and function. While the
process is essential for the expression of most genes, it is also one that is
subject to various forms of regulation, such that both quantitative and
qualitative aspects of gene expression may be modulated via the polyadenylation
complex. In this review, the current status of understanding of mRNA 3' end
formation in plants is discussed. In particular, the nature of mRNA 3' ends in
plants is reviewed, as are recent studies that are beginning to yield insight
into the functioning and regulation of plant polyadenylation factor subunits.
DOI: 10.1007/978-3-540-76776-3_9
PMID: 18630752 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31794245 | 1. Annu Rev Biochem. 2020 Jun 20;89:359-388. doi:
10.1146/annurev-biochem-091719-064225. Epub 2019 Dec 3.
RNA Splicing by the Spliceosome.
Wilkinson ME(1), Charenton C(1), Nagai K(1).
Author information:
(1)MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;
email: [email protected], [email protected].
The spliceosome removes introns from messenger RNA precursors (pre-mRNA).
Decades of biochemistry and genetics combined with recent structural studies of
the spliceosome have produced a detailed view of the mechanism of splicing. In
this review, we aim to make this mechanism understandable and provide several
videos of the spliceosome in action to illustrate the intricate choreography of
splicing. The U1 and U2 small nuclear ribonucleoproteins (snRNPs) mark an intron
and recruit the U4/U6.U5 tri-snRNP. Transfer of the 5' splice site (5'SS) from
U1 to U6 snRNA triggers unwinding of U6 snRNA from U4 snRNA. U6 folds with U2
snRNA into an RNA-based active site that positions the 5'SS at two catalytic
metal ions. The branch point (BP) adenosine attacks the 5'SS, producing a free
5' exon. Removal of the BP adenosine from the active site allows the 3'SS to
bind, so that the 5' exon attacks the 3'SS to produce mature mRNA and an excised
lariat intron.
DOI: 10.1146/annurev-biochem-091719-064225
PMID: 31794245 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20044349 | 1. Nucleic Acids Res. 2010 May;38(9):2757-74. doi: 10.1093/nar/gkp1176. Epub 2009
Dec 30.
Molecular mechanisms of eukaryotic pre-mRNA 3' end processing regulation.
Millevoi S(1), Vagner S.
Author information:
(1)Institut National de la Santé et de la Recherche Médicale U563, Toulouse,
F-31000, France. [email protected]
Messenger RNA (mRNA) 3' end formation is a nuclear process through which all
eukaryotic primary transcripts are endonucleolytically cleaved and most of them
acquire a poly(A) tail. This process, which consists in the recognition of
defined poly(A) signals of the pre-mRNAs by a large cleavage/polyadenylation
machinery, plays a critical role in gene expression. Indeed, the poly(A) tail of
a mature mRNA is essential for its functions, including stability, translocation
to the cytoplasm and translation. In addition, this process serves as a bridge
in the network connecting the different transcription, capping, splicing and
export machineries. It also participates in the quantitative and qualitative
regulation of gene expression in a variety of biological processes through the
selection of single or alternative poly(A) signals in transcription units. A
large number of protein factors associates with this machinery to regulate the
efficiency and specificity of this process and to mediate its interaction with
other nuclear events. Here, we review the eukaryotic 3' end processing
machineries as well as the comprehensive set of regulatory factors and discuss
the different molecular mechanisms of 3' end processing regulation by proposing
several overlapping models of regulation.
DOI: 10.1093/nar/gkp1176
PMCID: PMC2874999
PMID: 20044349 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28888105 | 1. Curr Opin Struct Biol. 2017 Oct;46:130-139. doi: 10.1016/j.sbi.2017.08.001.
Epub 2017 Sep 6.
CryoEM structures of spliceosomal complexes reveal the molecular mechanism of
pre-mRNA splicing.
Scheres SH(1), Nagai K(2).
Author information:
(1)MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH,
United Kingdom. Electronic address: [email protected].
(2)MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH,
United Kingdom. Electronic address: [email protected].
The spliceosome is an intricate molecular machine which catalyses the removal of
introns from eukaryotic mRNA precursors by two trans-esterification reactions
(branching and exon ligation) to produce mature mRNA with uninterrupted protein
coding sequences. The structures of the spliceosome in several key states
determined by electron cryo-microscopy have greatly advanced our understanding
of its molecular mechanism. The catalytic RNA core is formed during the
activation of the fully assembled B to Bact complex and remains largely
unchanged throughout the splicing cycle. RNA helicases and step specific factors
regulate docking and undocking of the substrates (branch site and 3' splice
site) to the single RNA-based active site to catalyse the two
trans-esterification reactions.
Copyright © 2017. Published by Elsevier Ltd.
DOI: 10.1016/j.sbi.2017.08.001
PMID: 28888105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25929182 | 1. Methods. 2015 Sep 1;85:36-43. doi: 10.1016/j.ymeth.2015.04.024. Epub 2015 Apr
27.
Quantification of co-transcriptional splicing from RNA-Seq data.
Herzel L(1), Neugebauer KM(2).
Author information:
(1)Molecular Biophysics and Biochemistry, Yale University, 333 Cedar St, New
Haven, CT 06520, United States.
(2)Molecular Biophysics and Biochemistry, Yale University, 333 Cedar St, New
Haven, CT 06520, United States. Electronic address: [email protected].
During gene expression, protein-coding transcripts are shaped by multiple
processing events: 5' end capping, pre-mRNA splicing, RNA editing, and 3' end
cleavage and polyadenylation. These events are required to produce mature mRNA,
which can be subsequently translated. Nearly all of these RNA processing steps
occur during transcription, while the nascent RNA is still attached to the DNA
template by RNA polymerase II (i.e. co-transcriptionally). Polyadenylation
occurs after 3' end cleavage or post-transcriptionally. Pre-mRNA splicing - the
removal of introns and ligation of exons - can be initiated and concluded
co-transcriptionally, although this is not strictly required. Recently, a number
of studies using global methods have shown that the majority of splicing is
co-transcriptional, yet not all published studies agree in their conclusions.
Short read sequencing of RNA (RNA-Seq) is the prevailing approach to measuring
splicing levels in nascent RNA, mRNA or total RNA. Here, we compare four
different strategies for analyzing and quantifying co-transcriptional splicing.
To do so, we reanalyze two nascent RNA-Seq datasets of the same species, but
different cell type and RNA isolation procedure. Average co-transcriptional
splicing values calculated on a per intron basis are similar, independent of the
strategy used. We emphasize the technical requirements for identifying
co-transcriptional splicing events with high confidence, e.g. how to calculate
co-transcriptional splicing from nascent RNA- versus mRNA-Seq data, the number
of biological replicates needed, depletion of polyA+RNA, and appropriate
normalization. Finally, we present guidelines for planning a nascent RNA-Seq
experiment.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ymeth.2015.04.024
PMID: 25929182 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36255686 | 1. Drugs. 2022 Sep;82(14):1489-1498. doi: 10.1007/s40265-022-01791-3. Epub 2022
Oct 18.
Cabotegravir Extended-Release Injectable Suspension: A Review in HIV-1
Pre-Exposure Prophylaxis.
Blair HA(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. [email protected].
Cabotegravir extended-release (ER) injectable suspension (Apretude™) is the
first long-acting injectable option to be approved for HIV-1 pre-exposure
prophylaxis (PrEP). As an HIV-1 integrase strand transfer inhibitor,
cabotegravir ER injectable suspension prevents DNA integration and inhibits
HIV-1 replication. Its slow absorption and long elimination half-life permit
infrequent dosing (1 month apart for two consecutive months, and every 2 months
thereafter). Cabotegravir ER injectable suspension is indicated in the USA for
PrEP to reduce the risk of sexually acquired HIV-1 infection in at-risk adults
and adolescents weighing ≥ 35 kg who have a negative HIV-1 test prior to
initiation. In clinical trials, cabotegravir ER injectable suspension had
superior efficacy to oral daily emtricitabine/tenofovir disoproxil fumarate (DF)
in preventing acquisition of HIV-1 in at-risk transgender women (TGW), cisgender
men who have sex with men (MSM), and cisgender women. The drug was generally
well tolerated, although further long-term data are needed to fully determine
its safety. With its convenient, less-frequent dosing schedule and its
long-acting formulation enabling intramuscular administration, cabotegravir ER
injectable suspension represents a novel and efficacious alternative to daily
oral PrEP.
Plain Language Summary: Despite major advances in the prevention of HIV-1
transmission, there remain barriers to the widespread effective use of
pre-exposure prophylaxis (PrEP). Approved daily oral PrEP requires people who do
not have HIV-1 to take a pill every day to protect them from acquiring the
infection. The availability of long-acting injectable PrEP that does not require
daily dosing has the potential to improve uptake and adherence, particularly in
high-risk individuals. Cabotegravir extended-release (ER) injectable suspension
is the first long-acting injectable option to be approved for PrEP, and is given
as an intramuscular injection as few as six times per year. Cabotegravir ER
injectable suspension is more effective than daily oral emtricitabine/tenofovir
disoproxil fumarate for preventing HIV-1 infection in adults who are at risk of
sexually acquiring HIV-1. Cabotegravir ER injectable suspension is generally
well tolerated and offers a convenient alternative to daily oral PrEP.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01791-3
PMID: 36255686 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35284988 | 1. CNS Drugs. 2022 Apr;36(4):401-410. doi: 10.1007/s40263-022-00910-8. Epub 2022
Mar 13.
Risdiplam: A Review in Spinal Muscular Atrophy.
Paik J(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. [email protected].
Risdiplam (Evrysdi®) is the first oral drug developed to treat spinal muscular
atrophy (SMA) and is approved in multiple countries worldwide. It is approved
for the treatment of SMA in patients aged ≥ 2 months in the USA and the EU, with
this approval further specified in the EU for the treatment of 5q-autosomal
recessive SMA with a clinical diagnosis of SMA types 1, 2, or 3 or with one to
four survival motor neuron 2 (SMN2) copies. As an SMN2 pre-mRNA splicing
modifier, risdiplam increases the production of full-length SMN protein, the
lack of which drives the pathophysiology of SMA. In phase 2/3 clinical trials,
risdiplam significantly improved motor function in infants with SMA type 1 and
in patients aged 2-25 years with SMA types 2 or 3. These motor improvements were
maintained with up to 2 years of treatment with risdiplam. Risdiplam was
generally well tolerated, with a favourable benefit to risk balance. As an oral
drug, risdiplam provides a convenient and useful treatment option across a broad
range of patient ages and subtypes of SMA.
Plain Language Summary: Patients with spinal muscular atrophy (SMA) have
insufficient levels of survival motor neuron (SMN) protein due to a defect in
the SMN1 gene. The SMN2 gene is also able to produce some SMN protein, but not
to the amount required to maintain adequate muscle function and form. Risdiplam
(Evrysdi®) is a drug that targets SMN2 to improve the production of viable SMN
protein and the first oral medication approved for the treatment of SMA. In the
FIREFISH and SUNFISH clinical trials, risdiplam improved motor function in
patients of all ages, with improvements maintained after 24 months of treatment.
Risdiplam was generally well tolerated in these trials, with a favourable
benefit to risk balance. As an orally administered treatment, risdiplam provides
a convenient and useful treatment option across a broad range of patient ages
and subtypes of SMA.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40263-022-00910-8
PMID: 35284988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33090613 | 1. Eur J Neurol. 2021 Feb;28(2):609-619. doi: 10.1111/ene.14587. Epub 2020 Nov
12.
Clinical and radiological profile of patients with spinal muscular atrophy type
4.
Souza PVS(1), Pinto WBVR(1), Ricarte A(2), Badia BML(1), Seneor DD(1), Teixeira
DT(2), Caetano L(2), Gonçalves EA(1), Chieia MAT(1), Farias IB(1), Bertini E(3),
Oliveira ASB(1).
Author information:
(1)Department of Neurology and Neurosurgery, Federal University of São Paulo
(UNIFESP), São Paulo, SP, Brazil.
(2)Neurotherapy Rehabilitation Center, São Paulo, SP, Brazil.
(3)Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù
Children's Research Hospital, IRCCS, Rome, Italy.
BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is the most important
cause of motor neuron disease in childhood, and continues to represent the
leading genetic cause of infant death. Adulthood-onset SMA (SMA type 4) is rare,
with few isolated cases reported. The objective of the present study was to
describe a cohort of patients with SMA type 4.
METHODS: A cross-sectional study was conducted to characterize clinical,
genetic, radiological and neurophysiological features of patients with
adulthood-onset SMA. Correlation analysis of functional assessment with genetic,
radiological and neurophysiological data was performed.
RESULTS: Twenty patients with SMA type 4 were identified in a Brazilian cohort
of 227 patients with SMA. The most common clinical symptom was limb-girdle
muscle weakness, observed in 15 patients (75%). The most frequent neurological
findings were absent tendon reflexes in 18 (90%) and fasciculations in nine
patients (45%). Sixteen patients (80%) had the homozygous deletion of exon 7 in
the SMN1 gene, with 12 patients (60%) showing four copies of the SMN2 gene. The
functional scales Hammersmith Functional Motor Scale Expanded, Amyotrophic
Lateral Sclerosis Functional Rating Scale Revised, Revised Upper Limb Module and
Spinal Muscular Atrophy Functional Rating Scale, as well as the six-minute walk
and the Time Up and Go tests showed a correlation with duration of disease.
Motor Unit Number Index was correlated both with duration of disease and with
performance in functional assessment. Radiological studies exhibited a typical
pattern, with involvement of biceps femoris short head and gluteus minimus in
all patients.
CONCLUSION: This study represents the largest cohort of patients with SMA type 4
and provides functional, genetic, radiological and neurophysiological features
that can be used as potential biomarkers for the new specific genetic therapies
for SMA.
© 2020 European Academy of Neurology.
DOI: 10.1111/ene.14587
PMID: 33090613 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35466947 | 1. J Neuromuscul Dis. 2022;9(3):397-409. doi: 10.3233/JND-210765.
Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in
Spinal Muscular Atrophy Types 3 and 4.
Habets LE(1), Bartels B(1), Asselman FL(2), Hulzebos EHJ(1), Stegeman DF(3),
Jeneson JAL(1), van der Pol WL(2).
Author information:
(1)Center for Child Development, Exercise and Physical Literacy, Wilhelmina
Children's Hospital, University Medical Center Utrecht, Utrecht, The
Netherlands.
(2)Department of Neurology and Neurosurgery, University Medical Center Utrecht
Brain Center, Utrecht University, Utrecht, The Netherlands.
(3)Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam,
Amsterdam, The Netherlands.
BACKGROUND: Exercise intolerance is an important impairment in patients with
SMA, but little is known about the mechanisms underlying this symptom.
OBJECTIVE: To investigate if reduced motor unit and capillary recruitment
capacity in patients with SMA contribute to exercise intolerance.
METHODS: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age-
and gender matched controls (n = 15) performed a maximal upper body exercise
test. We applied respiratory gas analyses, non-invasive surface electromyography
(sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen
consumption, arm muscle motor unit- and capillary recruitment, respectively.
RESULTS: Maximal exercise duration was twofold lower (p < 0.001) and work of
breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients
compared to controls, respectively. Regarding motor unit recruitment, we found
higher normalized RMS amplitude onset values of sEMG signals from all muscles
and the increase in normalized RMS amplitudes was similar in the m. triceps
brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls.
Median frequency, onset values were similar in patients and controls. We found a
similar decrease in median frequencies of sEMG recordings from the m. biceps
brachii, a diminished decrease from the m. brachioradialis and m. flexor
digitorum, but a larger decrease from the m. triceps brachii. With respect to
capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics
that were both qualitatively and quantitatively similar in patients and
controls.
CONCLUSION: We found no evidence for the contribution of motor unit and
capillary recruitment capacity of the upper arm muscles in adolescent and adult
patients with SMA types 3 and 4 as primary limiting factors to premature fatigue
during execution of a maximal arm-cycling task.
DOI: 10.3233/JND-210765
PMID: 35466947 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36335004 | 1. Brain Dev. 2023 Feb;45(2):110-116. doi: 10.1016/j.braindev.2022.10.006. Epub
2022 Nov 2.
Long-term efficacy of nusinersen and its evaluation in adolescent and adult
patients with spinal muscular atrophy types 1 and 2.
Iwayama H(1), Kawahara K(2), Takagi M(2), Numoto S(2), Azuma Y(2), Kurahashi
H(2), Yasue Y(3), Kawajiri H(3), Yanase A(3), Ito T(3), Kimura S(3), Kumagai
T(4), Okumura A(2).
Author information:
(1)Department of Pediatrics, Aichi Medical University School of Medicine,
Nagakute, Japan. Electronic address: [email protected].
(2)Department of Pediatrics, Aichi Medical University School of Medicine,
Nagakute, Japan.
(3)Department of Rehabilitation, Aichi Medical University School of Medicine,
Nagakute, Japan.
(4)Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital,
Kasugai, Japan; Kuma Home Medical Care Clinic, Nagoya, Japan.
BACKGROUNDS: The efficacy of nusinersen and its evaluation in patients with
spinal muscular atrophy (SMA) has been established in clinical trials only for
pediatric patients, not for adolescent and adult patients who developed SMA in
infancy or early childhood. We report a long-term follow-up in adolescent and
adult patients with SMA types 1 and 2.
METHODS: Nusinersen-treated patients with SMA types 1 and 2 between 2017 and
2022 were retrospectively reviewed. We compared baseline motor function tests
with those after the final treatment. Physical and occupational therapists
performed Children's Hospital of Philadelphia Infant Test of Neuromuscular
Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE),
and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not
performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4;
HFSME, 3; and RULM, 2.
RESULTS: Seven patients with SMA (type 1, 1; type 2, 6) with a median age of 23
(range, 12-40)years were treated with nusinersen for 3.55 (1.78-4.53)years.
Improvement was detected in CHOP-INTEND (pre, 5 [0-31]; post, 21 [0-39];
difference, 5 [0-26]; p = 0.100) without significance, although not in HFMSE
(pre, 0 [0-3]; post, 0 [0-5]; difference, 0 [0-2]; p = 0.346) and RULM (pre, 1
[0-20]; post, 3 [0-21]; difference, 1 [0-2]; p = 0.089). Owing to prolonged
treatment intervals with the COVID-19 pandemic, RULM worsened in two patients.
CONCLUSION: Nusinersen was effective in long-term follow-up. Only CHOP-INTEND
showed meaningful improvement. The interval between doses of nusinersen should
not be prolonged even with the COVID-19 pandemic.
Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier
B.V. All rights reserved.
DOI: 10.1016/j.braindev.2022.10.006
PMID: 36335004 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare the following financial interests/personal relationships which may be
considered as potential competing interests: HI received honoraria for 5
lectures (2019: 400,376 yen; 2020: 192,367 yen), and 2 manuscript writings
(2019: 175,307 yen). AO received honoraria for 1 speakers bureau (2019: 47,080
yen). The other authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/18304944 | 1. Nucleic Acids Res. 2008 Apr;36(7):2418-33. doi: 10.1093/nar/gkn080. Epub 2008
Feb 26.
Molecular dissection of mRNA poly(A) tail length control in yeast.
Viphakone N(1), Voisinet-Hakil F, Minvielle-Sebastia L.
Author information:
(1)Université Victor Segalen Bordeaux 2, CNRS, Institut de Biochimie et
Génétique Cellulaires, Bordeaux, France.
In eukaryotic cells, newly synthesized mRNAs acquire a poly(A) tail that plays
several fundamental roles in export, translation and mRNA decay. In mammals,
PABPN1 controls the processivity of polyadenylation and the length of poly(A)
tails during de novo synthesis. This regulation is less well-detailed in yeast.
We have recently demonstrated that Nab2p is necessary and sufficient for the
regulation of polyadenylation and that the Pab1p/PAN complex may act at a later
stage in mRNA metabolism. Here, we show that the presence of both Pab1p and
Nab2p in reconstituted pre-mRNA 3'-end processing reactions has no stimulating
nor inhibitory effect on poly(A) tail regulation. Importantly, the
poly(A)-binding proteins are essential to protect the mature mRNA from being
subjected to a second round of processing. We have determined which domains of
Nab2p are important to control polyadenylation and found that the RGG-box work
in conjunction with the two last essential CCCH-type zinc finger domains.
Finally, we have tried to delineate the mechanism by which Nab2p performs its
regulation function during polyadenylation: it likely forms a complex with
poly(A) tails different from a simple linear deposit of proteins as it has been
observed with Pab1p.
DOI: 10.1093/nar/gkn080
PMCID: PMC2367721
PMID: 18304944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35996994 | 1. Eur J Neurol. 2022 Dec;29(12):3556-3563. doi: 10.1111/ene.15528. Epub 2022 Sep
13.
Identification of UBA1 as the causative gene of an X-linked non-Kennedy
spinal-bulbar muscular atrophy.
Khani M(1)(2), Nafissi S(2)(3), Shamshiri H(2)(3), Moazzeni H(1), Taheri H(1),
Sadeghi M(4), Salehi N(5), Chitsazian F(6), Elahi E(1)(2).
Author information:
(1)School of Biology, College of Science, University of Tehran, Tehran, Iran.
(2)Iranian Neuromusclar Research Center, Tehran University of Medical Sciences,
Tehran, Iran.
(3)Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran.
(4)National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.
(5)School of Biological Science, Institute for Research in Fundamental Sciences
(IPM), Tehran, Iran.
(6)Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
BACKGROUND AND PURPOSE: Spinal-bulbar muscular atrophy (SBMA) (Kennedy's
disease) is a motor neuron disease. Kennedy's disease is nearly exclusively
caused by mutations in the androgen receptor encoding gene (AR). The results of
studies aimed at identification of the genetic cause of a disease that best
approximates SBMA in a pedigree (four patients) without mutations in AR are
reported.
METHODS: Clinical investigations included thorough neurological and
non-neurological examinations and testing. Genetic analysis was performed by
exome sequencing using standard protocols. UBA1 mutations were modeled on the
crystal structure of UBA1.
RESULTS: The clinical features of the patients are described in detail. A
missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable
cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on
chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like
modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the
ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause
infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation
identified here and the XL-SMA causative mutations were shown to affect amino
acids positioned in the vicinity of UBA1's ATP binding site and to cause
structural changes.
CONCLUSION: UBA1 was identified as a novel SBMA causative gene. The gene affects
protein homeostasis which is one of most important components of the pathology
of neurodegeneration. The contribution of this same gene to the etiology of
XL-SMA is discussed.
© 2022 European Academy of Neurology.
DOI: 10.1111/ene.15528
PMID: 35996994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34878390 | 1. Med Sci (Paris). 2021 Nov;37 Hors série n° 1:25-29. doi:
10.1051/medsci/2021187. Epub 2021 Dec 8.
[The SMA France national registry: already encouraging results].
[Article in French; Abstract available in French from the publisher]
Lemoine M(1), Gomez M(2), Grimaldi L(1), Urtizberea JA(3), Quijano-Roy S(4).
Author information:
(1)URC APHP Paris-Saclay, France.
(2)Centre de Référence des Maladies Neuromusculaires, Filnemus, Université Paris
Saclay, Garches, France - European Reference Center Network (Euro NMD ERN).
(3)European Reference Center Network (Euro NMD ERN).
(4)Institut de Myologie, Paris, France.
Spinal muscular atrophy is a debilitating neuromuscular disease due to the
deletion of the SMN1 gene (SMA). The emergence of innovative targeted therapies
changed the natural history of this condition. The French registry of SMA
(Registre SMA France) was launched in 2020 to obtain a better knowledge of the
pathology. The goal of the register was also to meet the need for real-life data
regarding the arrival of these innovative therapies in order to identify the
best therapeutic strategies and to improve patient care. The registry collects
retrospective and prospective data of all genetically confirmed SMA, treated or
not treated, in reference centers belonging to the national neuromuscular
network (FILNEMUS). The estimated enrollment is 1,000 patients (50% children).
On October 1st, 666 patients have been enrolled (357 children and 309 adults) by
44 out of 51 open centers of the national network (FILNEMUS) with: 150 type 1
(22%); 278 type 2 (42%), 232 type 3 (35%) and 4 type 4 (1%) respectively.
Publisher: TITLE: Le registre national SMA France : des résultats déjà
encourageants.
ABSTRACT: L’amyotrophie spinale proximale liée au gène SMN1 (SMA) est une
maladie neuromusculaire invalidante dont l’histoire naturelle a été sensiblement
modifiée ces dernières années du fait de l’apparition de thérapies innovantes.
Le registre SMA France a été mis en place en 2020 afin de mieux connaître la
pathologie et répondre au besoin de données en vie réelle induit par l’arrivée
de ces nouveaux médicaments. Le but est aussi d’essayer d’identifier les
meilleures stratégies thérapeutiques et d’améliorer in fine la prise en charge
de ces patients. Ce registre a le statut d’entrepôt de données de santé et
collecte des informations rétrospectives et prospectives de patients SMA de tous
types, génétiquement confirmés, traités ou non par thérapies innovantes, et
suivis dans les centres du réseau FILNEMUS. La population-cible est estimée à
1 000 patients, dont la moitié d’âge pédiatrique. Au 1er octobre 2021, 666
patients ont été inclus dans la base (357 enfants et 309 adultes) par 44 des 51
centres spécialisés du réseau neuromusculaire FILNEMUS ayant accepté de
participer. Parmi ces patients, 150 étaient de type 1 (22 %), 278 (42 %) de type
2, 232 (35 %) de type 3, et 4 de type 4 (1 %).
© 2021 médecine/sciences – Inserm.
DOI: 10.1051/medsci/2021187
PMID: 34878390 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27890489 | 1. Clin Nutr. 2017 Dec;36(6):1674-1680. doi: 10.1016/j.clnu.2016.10.020. Epub
2016 Nov 16.
Spinal Muscular Atrophy, types I and II: What are the differences in body
composition and resting energy expenditure?
Bertoli S(1), De Amicis R(2), Mastella C(3), Pieri G(4), Giaquinto E(4),
Battezzati A(2), Leone A(2), Baranello G(5).
Author information:
(1)International Center for the Assessment of Nutritional Status (ICANS),
Department of Food Environmental and Nutritional Sciences (DeFENS), University
of Milan, Milan, Italy. Electronic address: [email protected].
(2)International Center for the Assessment of Nutritional Status (ICANS),
Department of Food Environmental and Nutritional Sciences (DeFENS), University
of Milan, Milan, Italy.
(3)S.A.PRE., Early Habilitation Service, Mangiagalli e Regina Elena Hospital,
Milan, Italy.
(4)Dietetic and Nutrition Center, M. Bufalini Hospital, Cesena, Italy.
(5)Developmental Neurology Unit, Carlo Besta Neurological Institute Foundation,
Milan, Italy.
BACKGROUND & AIMS: Different neuromuscular functional domains in types I and II
Spinal Muscular Atrophy (SMAI and SMAII) could lead to differences in body
composition (BC) and resting energy expenditure (REE). Their identification
could provide the key to defining appropriate strategies in clinical dietary
management, but data comparing SMAI and SMAII in terms of BC and REE are not yet
available. We measured total and regional fat (FM), lean (LBM), mineral (BMC)
masses, body water (total, intra- and extra-cellular, TBW, ICW, ECW) and REE in
a sample of SMAI and II children, matched for age and sex, and also adjusting
for body size to compare these features of the two SMA phenotypes.
METHODS: 15 SMAI and 15 SMAII children, (M/F = 9/6 vs 9/6, age 3.6 ± 1.9 vs
3.5 ± 1.8 years, p = 0.99), confirmed genetically, were measured as follows:
Anthropometric measurements [Body Weight (BW), Supine Length (SL), Arm Length
(AL), Femur Length (FL), Tibia Length (TL)], Dual x-ray Energy Absorptiometry
(DEXA) [total and segmental FM, LBM, FFM, and BMC], Bioelectrical impedance
(BIA) [TBW, ICW, ECW] and Indirect Calorimetry (REE, respiratory quotients) were
collected by the same trained dietician. BW, SL and Body Mass Index (BMI)
Z-scores were calculated according to CDC Growth Charts (2000).
RESULTS: SMA children had high percentages of FM and a lower percentage of TBW
and ECW compared to the respective reference values for sex and age, whereas the
BMC percentages did not differ, even splitting the two phenotypes. SMA I
children had a lower BW and BMI-Z score compared to children with SMA II, but
similar total and segmental FM. On the contrary, total FFM and LBM were
significantly lower in SMAI (7290.0 ± 1729.1 g vs 8410.1 ± 1508.4 g;
6971.8 ± 1637.1 g vs 8041.7 ± 1427.7 g, p = 0.039, p = 0.037, respectively),
particularly at the trunk level. Arm BMC also resulted significantly lower in
SMAI. The measured REE values were similar (684 ± 143 kcal/day vs
703 ± 122 Kcal/day p = 0.707) whereas REE per FFM unit was higher in SMA I
children than in SMA II (95 ± 12 kcal/FFMkg vs 84 ± 11 kcal/FFMkg p = 0.017).
CONCLUSIONS: This study has shown that BW and BMI Z-score measurements alone can
be misleading in assessing nutritional status, particularly in SMAI. The
differences between SMAI and II in total and regional BC are related only to
FFM, LBM and BMC, and seem to be more linked to the magnitude of neurofunctional
impairment rather than to the nutritional status derangement. SMA I and SMA II
children can have different energy requirements in relation to their specific BC
and hypermetabolism of FFM. Based on these results, our recommendation is to use
direct BC and REE measurements in the nutritional care process until
SMA-specific predictive equations become available.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.clnu.2016.10.020
PMCID: PMC5681353
PMID: 27890489 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26260993 | 1. Pediatr Neurol. 2015 Oct;53(4):293-300. doi:
10.1016/j.pediatrneurol.2015.06.002. Epub 2015 Jun 10.
Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review.
Lin CW(1), Kalb SJ(2), Yeh WS(3).
Author information:
(1)University of Southern California, Los Angeles, California.
(2)Biogen, Cambridge, Massachusetts.
(3)Biogen, Cambridge, Massachusetts. Electronic address: [email protected].
BACKGROUND: Spinal muscular atrophy is a rare genetic disease with devastating
neurodegenerative consequences. Timing of diagnosis is crucial for spinal
muscular atrophy because early diagnosis may lead to early supportive care and
reduction in patient and caregiver stress. The purpose of this study was to
examine the published literature for diagnostic delay in spinal muscular
atrophy.
METHODS: A systematic literature search was conducted in the PubMed and Web of
Science databases for studies published between 2000 and 2014 that listed any
type of spinal muscular atrophy and without molecular, mouse, or pathology in
the keywords. Mean and/or median age of onset and diagnosis and delay in
diagnosis was extracted or calculated. All estimates were weighted by the number
of patients and descriptive statistics are reported.
RESULTS: A total of 21 studies were included in the final analysis. The weighted
mean (standard deviation) ages of onset were 2.5 (0.6), 8.3 (1.6), and 39.0
(32.6) months for spinal muscular atrophy types I, II, and III, respectively,
and the weighted mean (standard deviation) ages of confirmed spinal muscular
atrophy genetic diagnosis were 6.3 (2.2), 20.7 (2.6), and 50.3 (12.9) months,
respectively, for types I, II, and III. For studies reporting both age of onset
and diagnosis, the weighted diagnostic delay was 3.6, 14.3, and 43.6 months for
types I, II, and III, respectively.
CONCLUSIONS: Diagnostic delay is common in spinal muscular atrophy. The length
of delay varied by severity (type) of spinal muscular atrophy. Further studies
evaluating this delay and tools such as newborn screening are warranted to end
the diagnostic delay in spinal muscular atrophy.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pediatrneurol.2015.06.002
PMID: 26260993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14704958 | 1. J Neurobiol. 2004 Feb 5;58(2):272-86. doi: 10.1002/neu.10313.
Axonal defects in mouse models of motoneuron disease.
Jablonka S(1), Wiese S, Sendtner M.
Author information:
(1)Institute of Clinical Neurobiology, Josef-Schneider-Str. 11, D-97080
Wuerzburg, Germany.
Human motoneuron disease is characterized by loss of motor endplates, axonal
degeneration, and cell death of motoneurons. The identification of the
underlying gene defects for familial ALS, spinal muscular atrophy (SMA), and
spinal muscular atrophy with respiratory distress (SMARD) has pointed to
distinct pathophysiological mechanisms that are responsible for the various
forms of the disease. Accumulating evidence from mouse models suggests that
enhanced vulnerability and sensitivity to proapoptotic stimuli is only
responsible for some but not all forms of motoneuron disease. Mechanisms that
modulate microtubule assembly and the axonal transport machinery are defective
in several spontaneous and ENU (ethylnitrososurea) mutagenized mouse models but
also in patients with mutations in the p150 subunit of dynactin. Recent evidence
suggests that axonal growth defects contribute significantly to the
pathophysiology of spinal muscular atrophy. Reduced levels of the survival
motoneuron protein that are responsible for SMA lead to disturbed RNA processing
in motoneurons. This could also affect axonal transport of mRNAs for beta-actin
and other proteins that play an essential role in axon growth and synaptic
function. The local translation of specific proteins might be affected, because
developing motoneurons contain ribosome-like structures in distal axons and
growth cones. Altogether, the evidence from these mouse models and the new
genetic data from patients suggest that axon growth and maintenance involves a
variety of mechanisms, including microtubule assembly and axonal transport of
proteins and ribonucleoproteins (RNPs). Thus, defects in axon maintenance could
play a leading role in the development of several forms of human motoneuron
disease.
Copyright 2003 Wiley Periodicals, Inc.
DOI: 10.1002/neu.10313
PMID: 14704958 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33357591 | 1. Arch Pediatr. 2020 Dec;27(7S):7S15-7S17. doi: 10.1016/S0929-693X(20)30271-2.
Spinal muscular atrophy (SMA) type I (Werdnig-Hoffmann disease).
Audic F(1), Barnerias C(2).
Author information:
(1)Centre de Référence des Maladies Neuromusculaires de l'enfant PACARARE,
Service de Neuropédiatrie, Hôpital de la Timone Enfants, Marseille, France.
Electronic address: [email protected].
(2)Centre de Référence des Maladies Neuromusculaires Nord/Ile de France/Est,
Service de Neurologie pédiatrique, Hôpital Necker-Enfants Malades, APHP, Paris,
France. Electronic address: [email protected].
Spinal muscular atrophy type I, also called Werdnig-Hoffmann disease, is the
most serious form. The disease appears before the age of 6 months and is
characterized by major global hypotonia and abolition of tendon reflexes, with
children never being able to sit unaided. Cognitive development is normal and
the expressive gaze of these children contrasts with the paralytic attitude.
Respiratory involvement predominates in the intercostal muscles, and sometimes
brainstem involvement are all serious aspects of the disease. Type I spinal
muscular atrophy has been subdivided into 3 groups: - type IA, the clinical
signs of which set in between birth and 15 days of life with sudden severe motor
impairment, sucking-swallowing disorders attesting to bulbar involvement,
respiratory distress. - type IB with onset of symptoms before the age of 3
months, which implies no head control - type IC starting between 3 and 6 months
with the possibility of checking head control, often referred to as "I bis" by
French practitioners. The development and use of innovative therapies in recent
years does actually change the natural course of this disease. But we do not
know for sure what the long-term evolution of infants who received these new
therapies will be. © 2020 French Society of Pediatrics. Published by Elsevier
Masson SAS. All rights reserved.
Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS.
All rights reserved.
DOI: 10.1016/S0929-693X(20)30271-2
PMID: 33357591 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1389561 | 1. No To Shinkei. 1992 Jun;44(6):547-52.
[Clinical and histochemical findings in spinal muscular atrophy].
[Article in Japanese]
Fukunaga H(1), Moritoyo T, Okubo R, Higuchi I, Osame M.
Author information:
(1)Department of Neurology, National Minamikyusyu Hospital, Kagoshima, Japan.
The childhood form of the spinal muscular atrophy (SMA) is classically
subdivided into three groups on the basis of a combination of age of onset,
milestones of development and age of survival: acute Werdning-Hoffmann (type I),
intermediate Werdnig-Hoffmann (type II) and Kugelberg-Welander disease (type
III). Now we examined 7 cases of type I and 9 cases of type II on clinical and
histochemical ground. Of the total of 16 cases, 5 cases had a family history of
the disease. (1) In type I, three were males and 4 females. The onset was within
30 days and the disease was manifest before or at delivery in 3 cases. The
progression was so severe. All cases were dead by 10 months. They showed
generalized hypotonia, abnormal respiration and could not sit without support.
In type II, five were males and 4 females. The onset of the disease was between
the age of 3 and 15 months. The progression was slow. All patients couldn't walk
by themselves at all but 7 of them had abilities to sit without support.
Clinically it was easy to classify type I from type II. (2) The most
characteristic histochemical findings of both types were group atrophy, fiber
hypertrophy, fiber type predominance and fibrosis. Though there was a slight
difference between two types in histological pattern, the basis was so similar.
There is controversy about the proper classification of recessive childhood SMA.
Now it is suggested that the majority of both acute and chronic cases are
allelic, similar to the patterns of Duchenne and Becker forms of muscular
dystrophy.
PMID: 1389561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33357593 | 1. Arch Pediatr. 2020 Dec;27(7S):7S23-7S28. doi: 10.1016/S0929-693X(20)30273-6.
Clinical features of spinal muscular atrophy (SMA) type 3 (Kugelberg-Welander
disease).
Salort-Campana E(1), Quijano-Roy S(2).
Author information:
(1)Centre de référence PACA Réunion Rhône Alpes, La Timone University Hospital,
Aix-Marseille University, Marseille, France; Aix Marseille University, INSERM,
GMGF, Marseille, France; FILNEMUS.
(2)FILNEMUS; Unité Neuromusculaire de l'Enfant, Service de Neurologie et
Réanimation Pédiatrique, Hôpital Raymond Poincaré (GH APHP Université Paris
Saclay), Garches, France; UMR 1179 Handicap neuromusculaire : Physiopathologie,
Biothérapie et Pharmacologie appliquées (END-ICAP) - UMR U1179 (INSERM/UVSQ);
Centre de Référence Nord-Est-Ile de France. Electronic address:
[email protected].
Spinal muscular atrophy type 3 (SMA3), also called Kugelberg-Welander SMA,
typically presents with muscle fatigue, slowly progressive weakness and atrophy
of lower limbs once they have already acquired independent ambulation. Visceral
involvement frequent in type 1 and 2 subtypes is rare in SMA3. Hypotonia,
hyperlaxity and absent osteo-tendinous reflexes are typical features. By
definition, standing or walking without support is achieved but the vast
majority of SMA3 patients lose ambulation with time. Lifespan is normal. In some
classifications, an additional subtype is included in the mild end of the
spectrum, namely spinal muscular atrophy type 4 (SMA4). In this rare subtype,
symptoms begin in adulthood; patients remain ambulatory at least until the fifth
decade and have a normal respiratory function. Molecular genetic testing is the
gold standard tool for diagnosis of SMA. However, diagnosis in a child affected
with SMA3 is often challenging because clinical presentation mimics a muscular
dystrophy. Electrodiagnostic studies and muscle biopsy are useful tools for
demonstrating the presence of denervation but sometimes may not show meaningful
differences to help distinguish between SMA and myopathy. Recent specific
therapies show promising results before severe neuronal degeneration and motor
dysfunction is installed. Therefore, high suspicion should be maintained and
genetic analysis performed early in the diagnostic process when facing patients
with symmetric and prominent proximal weakness, especially if they present
progressive motor impairment. © 2020 French Society of Pediatrics. Published by
Elsevier Masson SAS. All rights reserved.
Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS.
All rights reserved.
DOI: 10.1016/S0929-693X(20)30273-6
PMID: 33357593 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35707597 | 1. Mol Syndromol. 2022 May;13(3):246-253. doi: 10.1159/000519640. Epub 2022 Feb
4.
X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the UBA1 Gene
in a Family with Novel Findings from Turkey.
Öztürk Ö(1), Çavdartepe BE(2), Bağış H(1).
Author information:
(1)Department of Medical Genetics, Medical Faculty, Adiyaman University,
Adiyaman, Turkey.
(2)Department of Medical Genetics, Adiyaman University Training and Research
Hospital, Adiyaman, Turkey.
Spinal muscular atrophy, X-linked 2 (SMAX2) is a rare type of spinal muscular
atrophy characterized by muscle weakness, hypotonia, areflexia, myopathic face,
tongue fibrillations, contractures, bone fractures, and cryptorchidism. Variants
of the UBA1 gene lead to SMAX2. The UBA1 gene encodes a protein that activates
the ubiquitin pathway which is responsible for protein degradation. Here, we
describe a family presenting with hypotonia, muscle weakness, areflexia,
contractures, weak cry, in association with other anomalies including myopathic
face, scoliosis, tongue fibrillations, and cryptorchidism. Molecular analysis in
2 patients revealed a hemizygous pathogenic variant in the UBA1 gene
(NM_153280.3, NP_695012.1: c.1731C>T [p.Asn577Asn]) inherited from their carrier
mothers. Our study presents the first patients from Turkey, widening the
phenotypic spectrum of SMAX2 by pectus carinatum, medullary sponge kidney, and
frontal cyst.
Copyright © 2022 by S. Karger AG, Basel.
DOI: 10.1159/000519640
PMCID: PMC9149478
PMID: 35707597
Conflict of interest statement: The authors report no conflicts of interest. The
authors alone are responsible for the content and writing of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/16865356 | 1. Neurogenetics. 2006 Nov;7(4):269-76. doi: 10.1007/s10048-006-0051-3. Epub 2006
Jul 22.
Spinal muscular atrophy genotyping by gene dosage using multiple
ligation-dependent probe amplification.
Scarciolla O(1), Stuppia L, De Angelis MV, Murru S, Palka C, Giuliani R, Pace M,
Di Muzio A, Torrente I, Morella A, Grammatico P, Giacanelli M, Rosatelli MC,
Uncini A, Dallapiccola B.
Author information:
(1)Dipartimento di Scienze Biomediche, Sezione di Genetica Medica, Università G.
dAnnunzio, Via dei Vestini 35, Chieti-Pescara, 66013, Italy.
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by
degeneration of the anterior horn cells of the spinal cord, causing symmetric
proximal muscle weakness. SMA is classified in three clinical types, SMA I, SMA
II, and SMA III, based on the severity of the symptoms and the age of onset.
About 95% of SMA cases are caused by homozygous deletion of the survival motor
neuron 1 (SMN1) gene (5q13), or its conversion to SMN2. The molecular diagnosis
of this disease is usually carried out by a polymerase chain
reaction-restriction fragment length polymorphism approach able to evidence the
absence of both SMN1 copies. However, this approach is not able to identify
heterozygous healthy carriers, which show a very high frequency in general
population (1:50). We used the multiple ligation-dependent probe amplification
(MLPA) approach for the molecular diagnosis of SMA in 19 affected patient and in
57 individuals at risk to become healthy carriers. This analysis detected the
absence of the homozygous SMN1 in all the investigated cases, and allowed to
discriminate between SMN1 deletion and conversion to SMN2 on the basis of the
size showed by the peaks specific for the different genes mapped within the SMA
critical region. Moreover, MLPA analysis evidenced a condition of the absence of
the heterozygous SMN1 in 33 out of the 57 relatives of the affected patients,
demonstrating the usefulness of this approach in the identification of healthy
carriers. Thus, the MLPA technique represents an easy, low cost, and high
throughput system in the molecular diagnosis of SMA, both in affected patients
and in healthy carriers.
DOI: 10.1007/s10048-006-0051-3
PMID: 16865356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35779372 | 1. Mult Scler Relat Disord. 2022 Sep;65:104002. doi: 10.1016/j.msard.2022.104002.
Epub 2022 Jun 25.
Outcomes of Ublituximab compared to Teriflunomide for relapsing multiple
sclerosis: A meta-analysis.
Mukhtar H(1), Yasmeen U(2), Siddiqa S(3), Sarfraz Z(4), Sarfraz A(5).
Author information:
(1)Independent Medical College, Faisalabad, Pakistan.
(2)Faisalabad Medical University, Faisalabad, Pakistan.
(3)Ameer Ud Din Medical College, Lahore, Pakistan.
(4)Fatima Jinnah Medical University, Lahore, Punjab 54000, Pakistan. Electronic
address: [email protected].
(5)Aga Khan University, Karachi, Pakistan.
Ublituximab is an anti-CD20 antibody that immunomodulates B-cells for relapsing
multiple sclerosis (MS). With limited therapeutics available, this original
meta-analysis seeks to determine the effect size (using RevMan 5.4.1) for
annualized relapse rate (ARR), MRI outcomes and no evidence of disease activity
(NEDA) by two years post-initiation of Ublituximab. Two RCTs (N = 1094) reveal
Cohen's d for ARR= -0.17 (P = 0.006) favoring Ublituximab. MRI-tested, week 96
findings of T1 (Cohen's d= -0.43, P < 0.00001) and T2 (Cohen's d= -0.55;
P < 0.00001) lesions favor Ublituximab compared to Teriflunomide. Less disease
activity was reported in the Ublituximab group (OR=3.33, P < 0.00001). Further
trials are required to corroborate findings.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.msard.2022.104002
PMID: 35779372 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35570581 | 1. Can J Neurol Sci. 2023 May;50(3):355-364. doi: 10.1017/cjn.2022.60. Epub 2022
May 16.
B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment.
Kanatas P(1)(2), Stouras I(1), Stefanis L(1)(2), Stathopoulos P(1)(2).
Author information:
(1)First Department of Neurology, School of Medicine, National Kapodistrian
University of Athens, Athens, Greece.
(2)Eginiteion Hospital, Athens, Greece.
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the
central nervous system (CNS) that often progresses to severe disability.
Previous studies have highlighted the role of T cells in disease
pathophysiology; however, the success of B-cell-targeted therapies has led to an
increased interest in how B cells contribute to disease immunopathology. In this
review, we summarize evidence of B-cell involvement in MS disease mechanisms,
starting with pathology and moving on to review aspects of B cell immunobiology
potentially relevant to MS. We describe current theories of critical B cell
contributions to the inflammatory CNS milieu in MS, namely (i) production of
autoantibodies, (ii) antigen presentation, (iii) production of proinflammatory
cytokines (bystander activation), and (iv) EBV involvement. In the second part
of the review, we summarize medications that have targeted B cells in patients
with MS and their current position in the therapeutic armamentarium based on
clinical trials and real-world data. Covered therapeutic strategies include the
targeting of surface molecules such as CD20 (rituximab, ocrelizumab, ofatumumab,
ublituximab) and CD19 (inebilizumab), and molecules necessary for B-cell
activation such as B cell activating factor (BAFF) (belimumab) and Bruton's
Tyrosine Kinase (BTK) (evobrutinib). We finally discuss the use of
B-cell-targeted therapeutics in pregnancy.
DOI: 10.1017/cjn.2022.60
PMID: 35570581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35869335 | 1. CNS Drugs. 2022 Aug;36(8):803-817. doi: 10.1007/s40263-022-00939-9. Epub 2022
Jul 22.
Efficacy and Safety of Multiple Sclerosis Drugs Approved Since 2018 and Future
Developments.
Faissner S(1), Gold R(2).
Author information:
(1)Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital,
Gudrunstr. 56, 44791, Bochum, Germany. [email protected].
(2)Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital,
Gudrunstr. 56, 44791, Bochum, Germany.
Multiple sclerosis treatment made substantial headway during the last two
decades with the implementation of therapeutics with new modes of action and
routes of application. We are now in the situation that second-generation
molecules, approved since 2018, are on the market, characterized by reduced side
effects using a more tailored therapeutic approach. Diroximel fumarate is a
second-generation fumarate with reduced gastrointestinal side effects. Moreover,
several novel, selective, sphingosine-1-phosphate receptor modulators with
reduced off-target effects have been developed; namely siponimod, ozanimod, and
ponesimod; all oral formulations. B-cell-targeted therapies such as ocrelizumab,
given intravenously, and since 2021 ofatumumab, applied subcutaneously,
complement the spectrum of novel therapies. The glycoengineered antibody
ublituximab is the next anti-CD20 therapy about to be approved. Within the next
years, oral inhibitors of Bruton's tyrosine kinase, currently under
investigation in several phase III trials, may be licensed for multiple
sclerosis. Those developments currently offer an individualized multiple
sclerosis therapy, targeting patient needs with substantial effects on relapses,
disability progression, and implications for daily life. In this up-to-date
review, we provide a holistic overview about novel developments of the
therapeutic landscape and upcoming approaches for multiple sclerosis treatment.
© 2022. The Author(s).
DOI: 10.1007/s40263-022-00939-9
PMCID: PMC9307218
PMID: 35869335 [Indexed for MEDLINE]
Conflict of interest statement: Simon Faissner and Ralf Gold have no conflicts
of interest that are directly relevant to the content of this article. Simon
Faissner has received speaker’s and/or scientific board honoraria from Biogen,
BMS, Celgene, Genesis Pharma, Novartis, and Roche and grant support from
Ruhr-University Bochum, DMSG, Stiftung für therapeutische Forschung, Lead
Discovery Center GmbH, and Novartis. Ralf Gold serves on scientific advisory
boards for Teva Pharmaceutical Industries Ltd., Biogen, Bayer Schering Pharma,
and Novartis; has received speaker honoraria from Biogen, Teva Pharmaceutical
Industries Ltd., Bayer Schering Pharma, and Novartis; serves as an editor for
Therapeutic Advances in Neurological Diseases and on the editorial boards of
Experimental Neurology and the Journal of Neuroimmunology; and receives research
support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering
Pharma, Genzyme, Merck Serono, and Novartis. |
http://www.ncbi.nlm.nih.gov/pubmed/3830522 | 1. Clin Rheumatol. 1985 Dec;4(4):449-51. doi: 10.1007/BF02031898.
Palmar erythema in rheumatoid arthritis.
Saario R, Kalliomäki JL.
Palmar erythema ("liver palms") was seen in 32/100 consecutive patients with
classical rheumatoid arthritis and in 10/100 patients with various other
internal diseases (p less than 0.001). Age of the patients, sex, duration of
disease, titer of rheumatoid factor, stage of disease, erythrocyte sedimentation
rate and frequency of volar tenosynovitis of the hands did not differ between
patients with and those without palmar erythema. Ulnar deviation of the fingers
was less common and the hemoglobin content of the blood was higher in patients
with palmar erythema.
DOI: 10.1007/BF02031898
PMID: 3830522 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35378683 | 1. Neurotherapeutics. 2022 Apr;19(3):753-773. doi: 10.1007/s13311-022-01224-9.
Epub 2022 Apr 4.
Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an
Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.
Krajnc N(#)(1), Bsteh G(#)(1), Berger T(1), Mares J(2), Hartung HP(3)(4)(5)(6).
Author information:
(1)Department of Neurology, Medical University of Vienna, Vienna, Austria.
(2)Department of Neurology, Palacky University Olomouc, Olomouc, Czech Republic.
(3)Department of Neurology, Medical University of Vienna, Vienna, Austria.
[email protected].
(4)Department of Neurology, Palacky University Olomouc, Olomouc, Czech Republic.
[email protected].
(5)Department of Neurology, Medical Faculty, Heinrich-Heine University,
Moorenstrasse 5, 40225, Düsseldorf, Germany.
[email protected].
(6)Brain and Mind Center, University of Sydney, Sydney, Australia.
[email protected].
(#)Contributed equally
Monoclonal antibodies have become a mainstay in the treatment of patients with
relapsing multiple sclerosis (RMS) and provide some benefit to patients with
primary progressive MS. They are highly precise by specifically targeting
molecules displayed on cells involved in distinct immune mechanisms of MS
pathophysiology. They not only differ in the target antigen they recognize but
also by the mode of action that generates their therapeutic effect. Natalizumab,
an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via
binding to cell surface receptors, blocking the interaction with their ligands
and, in that way, preventing the migration of leukocytes across the blood-brain
barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and
the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and
ublituximab work via eliminating selected pathogenic cell populations. However,
potential adverse effects may be serious and can necessitate treatment
discontinuation. Most importantly, those are the risk for (opportunistic)
infections, but also secondary autoimmune diseases or malignancies. Monoclonal
antibodies also carry the risk of infusion/injection-related reactions,
primarily in early phases of treatment. By careful patient selection and
monitoring during therapy, the occurrence of these potentially serious adverse
effects can be minimized. Monoclonal antibodies are characterized by a
relatively long pharmacologic half-life and pharmacodynamic effects, which
provides advantages such as permitting infrequent dosing, but also creates
disadvantages regarding vaccination and family planning. This review presents an
overview of currently available monoclonal antibodies for the treatment of RMS,
including their mechanism of action, efficacy and safety profile. Furthermore,
we provide practical recommendations for risk management, vaccination, and
family planning.
© 2022. The Author(s).
DOI: 10.1007/s13311-022-01224-9
PMCID: PMC8978776
PMID: 35378683 [Indexed for MEDLINE]
Conflict of interest statement: Nik Krajnc has participated in meetings
sponsored by, received speaker honoraria or travel funding from Roche, Novartis,
and Merck and holds a grant for a Multiple Sclerosis Clinical Training
Fellowship Programme from the European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS). Gabriel Bsteh has participated in meetings
sponsored by, received speaker honoraria or travel funding from Biogen, Celgene,
Lilly, Merck, Novartis, Sanofi-Genzyme, and Teva and received honoraria for
consulting Biogen, Celgene, Novartis, Sanofi-Genzyme, Roche, and Teva. Thomas
Berger has participated in meetings sponsored by and received honoraria
(lectures, advisory boards, consultations) from pharmaceutical companies
marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene,
MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. His
institution has received financial support in the past 12 months by unrestricted
research grants (Biogen, Bayer, Merck, Novartis, Sanofi Aventis, Teva and for
participation in clinical trials in multiple sclerosis sponsored by Alexion,
Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. Jan
Mares declares no conflict of interest relevant to this manuscript. Hans-Peter
Hartung has participated in meetings sponsored by and received honoraria
(lectures, advisory boards, consultations) from pharmaceutical companies
marketing treatments for MS: Alexion, Bayer, Biogen, Bristol Myers Squibb,
GeNeuro, Horizon Therapeutics, Merck, Novartis, Octapharma, Roche, TG
Therapeutics, UCB. |
http://www.ncbi.nlm.nih.gov/pubmed/36001711 | 1. N Engl J Med. 2022 Aug 25;387(8):704-714. doi: 10.1056/NEJMoa2201904.
Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.
Steinman L(1), Fox E(1), Hartung HP(1), Alvarez E(1), Qian P(1), Wray S(1),
Robertson D(1), Huang D(1), Selmaj K(1), Wynn D(1), Cutter G(1), Mok K(1), Hsu
Y(1), Xu Y(1), Weiss MS(1), Bosco JA(1), Power SA(1), Lee L(1), Miskin HP(1),
Cree BAC(1); ULTIMATE I and ULTIMATE II Investigators.
Collaborators: Kulesh S, Holets Y, Alekseenko Y, Navumava H, Ponomarev V,
Fedulau A, Zabrodzets G, Zubonja TM, Kidjemet Piskac S, Habek M, Mania M,
Guldedava N, Janelidze M, Gauarashvili A, Kiziria M, Shakarishvili R,
Tsiskaridze A, Szczudlik A, Motta E, Stepien A, Ilkowski J, Tutaj A, Krzystanek
E, Zaborski J, Zbrojkiewicz J, Selmaj K, Adamczyk-Sowa M, Yurchenko A,
Khachanova N, Bakhtiyarova K, Stolyarov I, Sivertseva S, Mishin G, Dorogov N,
Sazonov D, Alifirova V, Malkova N, Volkova L, Patrusheva O, Arefyeva E, Belova
A, Karpov D, Totolyan N, Laskov V, Makshakov G, Lukyanchikova L, Zakharova M,
Pokhabov D, Maslova N, Boskovic-Matic T, Drulovic J, Smiljkovic T, Dincic E,
Casanova B, Gascon F, Arroyo Gonzalez R, Rodriguez Antiguedad A, Martinez
Yelamos S, Montalban X, Muratova T, Kareta S, Drobotenko V, Kadina L, Nehrych T,
Loganovskyi K, Lytvynenko N, Smolanka V, Khavunka M, Tovazhnyanska O,
Pashkovskyy V, Pasiura I, Ihnatenko I, Neryanova Y, Pryshchepa V, Chmyr G,
Hrebeniuk H, Moskovko S, Shkrobot S, Cherkez A, Carod-Artal FJ, Rog D, Robertson
N, Hunter S, Fox E, Huang D, Wynn D, Mazhari A, Wray S, Okai A, Shubin R,
Frishberg B, Lynch S, Rammohan K, Bernitsas E, Hua L, Picone MA, Evans E, Eubank
G, Gudesblatt M, Qian P, Alvarez E, Ford C, Robertson D.
Author information:
(1)From the Beckman Center for Molecular Medicine, Stanford University, Stanford
(L.S.), and the Weill Institute for Neurosciences, University of California, San
Francisco, San Francisco (B.A.C.C.) - both in California; Central Texas
Neurology Consultants, Round Rock (E.F.); Heinrich Heine University Medical
School, Düsseldorf, Germany (H.-P.H.); the Brain and Mind Centre, University of
Sydney, Sydney (H.-P.H.); Medical University of Vienna, Vienna (H.-P.H.);
Palacký University Olomouc, Olomouc, Czech Republic (H.-P.H.); University of
Colorado, Aurora (E.A.); Swedish Medical Center, Seattle (P.Q.); Hope Neurology,
Knoxville, TN (S.W.); University of South Florida, Tampa (D.R.); Columbus
Neuroscience, Westerville, OH (D.H.); the Department of Neurology, University of
Warmia and Mazury, Olsztyn, and Center of Neurology, Lodz - both in Poland
(K.S.); Consultants in Neurology, Northbrook, IL (D.W.); and TG Therapeutics,
New York (G.C., K.M., Y.H., Y.X., M.S.W., J.A.B., S.A.P., L.L., H.P.M.).
BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent
cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated
for the treatment of relapsing multiple sclerosis.
METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE
I and II), participants with relapsing multiple sclerosis were randomly assigned
in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by
450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral
teriflunomide (14 mg once daily) and intravenous placebo. The primary end point
was the annualized relapse rate. Secondary end points included the number of
gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and
worsening of disability.
RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and
545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks.
In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab
and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI],
0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate
was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78;
P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the
ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI,
0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively
(rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In
the pooled analysis of the two trials, 5.2% of the participants in the
ublituximab group and 5.9% in the teriflunomide group had worsening of
disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51).
Infusion-related reactions occurred in 47.7% of the participants in the
ublituximab group. Serious infections occurred in 5.0% in the ublituximab group
and in 2.9% in the teriflunomide group.
CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab
resulted in lower annualized relapse rates and fewer brain lesions on MRI than
teriflunomide over a period of 96 weeks but did not result in a significantly
lower risk of worsening of disability. Ublituximab was associated with
infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II
ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2201904
PMID: 36001711 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22474732 | 1. Cutis. 2012 Feb;89(2):84-8.
Palmar telangiectases as a manifestation of Graves disease.
Nabatian A(1), Suchter MF, Milgraum S.
Author information:
(1)UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
[email protected]
Telangiectases are lesions formed by persistent segmental dilatation of
papillary plexus vessels of the skin that typically present as fine, bright,
nonpulsatile red lines or netlike patterns. Palmar erythema commonly presents as
symmetric, blanchable, slightly warm, nonscaling erythema, most frequently
involving the thenar and hypothenar eminences of the palmar surface. Palmar
telangiectases and palmar erythema both have primary cutaneous, systemic
disease, neoplastic, infectious, and drug-induced etiologies. We describe a case
of palmar telangiectases in a patient with Graves disease. We also describe the
pathophysiology of palmar telangiectases and palmar erythema and present a
literature review of their etiologies.
PMID: 22474732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26216216 | 1. Hum Genomics. 2015 Jul 28;9(1):17. doi: 10.1186/s40246-015-0041-3.
Epigenetic inheritance and the missing heritability.
Trerotola M(1), Relli V(2), Simeone P(3), Alberti S(4)(5).
Author information:
(1)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(2)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(3)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(4)Unit of Cancer Pathology, CeSI, Foundation University 'G. d'Annunzio',
Chieti, Italy. [email protected].
(5)Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology
and Physiopathology, 'G. d'Annunzio' University, Chieti, Italy.
[email protected].
Genome-wide association studies of complex physiological traits and diseases
consistently found that associated genetic factors, such as allelic
polymorphisms or DNA mutations, only explained a minority of the expected
heritable fraction. This discrepancy is known as "missing heritability", and its
underlying factors and molecular mechanisms are not established. Epigenetic
programs may account for a significant fraction of the "missing heritability."
Epigenetic modifications, such as DNA methylation and chromatin assembly states,
reflect the high plasticity of the genome and contribute to stably alter gene
expression without modifying genomic DNA sequences. Consistent components of
complex traits, such as those linked to human stature/height, fertility, and
food metabolism or to hereditary defects, have been shown to respond to
environmental or nutritional condition and to be epigenetically inherited. The
knowledge acquired from epigenetic genome reprogramming during development, stem
cell differentiation/de-differentiation, and model organisms is today shedding
light on the mechanisms of (a) mitotic inheritance of epigenetic traits from
cell to cell, (b) meiotic epigenetic inheritance from generation to generation,
and (c) true transgenerational inheritance. Such mechanisms have been shown to
include incomplete erasure of DNA methylation, parental effects, transmission of
distinct RNA types (mRNA, non-coding RNA, miRNA, siRNA, piRNA), and persistence
of subsets of histone marks.
DOI: 10.1186/s40246-015-0041-3
PMCID: PMC4517414
PMID: 26216216 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32319122 | 1. Bioessays. 2020 Jul;42(7):e1900254. doi: 10.1002/bies.201900254. Epub 2020 Apr
22.
Heritable Epigenetic Changes Alter Transgenerational Waveforms Maintained by
Cycling Stores of Information.
Jose AM(1).
Author information:
(1)Department of Cell Biology and Molecular Genetics, University of Maryland,
College Park, MD, 20742, USA.
Our view of heredity can potentially be distorted by the ease of introducing
heritable changes in the replicating gene sequences but not in the cycling
assembly of regulators around gene sequences. Here, key experiments that have
informed the understanding of heredity are reinterpreted to highlight this
distortion and the possible variety of heritable changes are considered. Unlike
heritable genetic changes, which are always associated with mutations in gene
sequence, heritable epigenetic changes can be associated with physical or
chemical changes in molecules or only changes in the system. The transmission of
cycling stores along the continuous lineage of cells that connects successive
generations creates waves of activity and localization of the molecules that
together form the cell code for development in each generation. As a result,
heritable epigenetic changes can include any that can alter a wave such as
changes in form, midline, frequency, amplitude, or phase. Testing this
integrated view of all heritable information will require the concerted
application of multiple experimental approaches across generations.
© 2020 WILEY Periodicals, Inc.
DOI: 10.1002/bies.201900254
PMCID: PMC7359639
PMID: 32319122 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest The author has declared no
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32868918 | 1. Nat Ecol Evol. 2020 Nov;4(11):1539-1548. doi: 10.1038/s41559-020-01293-z. Epub
2020 Aug 31.
Epimutations driven by small RNAs arise frequently but most have limited
duration in Caenorhabditis elegans.
Beltran T(1)(2), Shahrezaei V(3), Katju V(4), Sarkies P(5)(6).
Author information:
(1)MRC London Institute of Medical Sciences, London, UK.
(2)Institute of Clinical Sciences, Imperial College London, London, UK.
(3)Department of Mathematics, Faculty of Natural Sciences, Imperial College
London, London, UK.
(4)Department of Veterinary Integrative Biosciences, Texas A&M University,
College Station, TX, USA.
(5)MRC London Institute of Medical Sciences, London, UK.
[email protected].
(6)Institute of Clinical Sciences, Imperial College London, London, UK.
[email protected].
Epigenetic regulation involves changes in gene expression independent of DNA
sequence variation that are inherited through cell division. In addition to a
fundamental role in cell differentiation, some epigenetic changes can also be
transmitted transgenerationally through meiosis. Epigenetic alterations
(epimutations) could thus contribute to heritable variation within populations
and be subject to evolutionary processes such as natural selection and drift.
However, the rate at which epimutations arise and their typical persistence are
unknown, making it difficult to evaluate their potential for evolutionary
adaptation. Here, we perform a genome-wide study of epimutations in a metazoan
organism. We use experimental evolution to characterize the rate, spectrum and
stability of epimutations driven by small silencing RNAs in the model nematode
Caenorhabditis elegans. We show that epimutations arise spontaneously at a rate
approximately 25 times greater than DNA sequence changes and typically have
short half-lives of two to three generations. Nevertheless, some epimutations
last at least ten generations. Epimutations mediated by small RNAs may thus
contribute to evolutionary processes over a short timescale but are unlikely to
bring about long-term divergence in the absence of selection.
DOI: 10.1038/s41559-020-01293-z
PMID: 32868918 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21734376 | 1. Dig Dis. 2011;29(2):130-5. doi: 10.1159/000323874. Epub 2011 Jul 5.
Epigenetics: principles and practice.
Hamilton JP(1).
Author information:
(1)Division of Gastroenterology and Hepatology, The Johns Hopkins University
School of Medicine, Baltimore, MD 21205, USA. [email protected]
Epigenetics is defined as heritable changes in gene expression that are, unlike
mutations, not attributable to alterations in the sequence of DNA. The
predominant epigenetic mechanisms are DNA methylation, modifications to
chromatin, loss of imprinting and non-coding RNA. Epigenetic regulation of gene
expression appears to have long-term effects and wide-ranging effects on health.
Diet and environmental exposures may potentially alter the level and scope of
epigenetic regulation, thus interesting developments in the study of epigenetics
might explain correlations that researchers have found between lifestyle and
risk of disease. Aberrant epigenetic patterns have been linked to a number of
digestive diseases including Barrett's esophagus, cirrhosis, inflammatory bowel
disease, and numerous gastrointestinal malignancies. In fact, many exciting
discoveries about epigenetics in general have been made by studying diseases of
the gastrointestinal tract and hepatobiliary tree. Epigenetic modifications of
DNA in cancer and precancerous lesions offer hope and the promise of novel
biomarkers for early cancer detection, prediction, prognosis, and response to
treatment. Furthermore, reversal of epigenetic changes represents a potential
target of novel therapeutic strategies and medication design. In the future, it
is anticipated that innovative diagnostic tests, treatment regimens, and even
lifestyle modifications will be based on epigenetic mechanisms and be
incorporated into the practice of medicine.
Copyright © 2011 S. Karger AG, Basel.
DOI: 10.1159/000323874
PMCID: PMC3134032
PMID: 21734376 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25778758 | 1. Prog Biophys Mol Biol. 2015 Jul;118(1-2):69-78. doi:
10.1016/j.pbiomolbio.2015.02.009. Epub 2015 Mar 14.
Insects as models to study the epigenetic basis of disease.
Mukherjee K(1), Twyman RM(2), Vilcinskas A(3).
Author information:
(1)Fraunhofer Institute for Molecular Biology and Applied Ecology, Department of
Bioresources, Winchester Str. 2, 35394 Giessen, Germany. Electronic address:
[email protected].
(2)TRM Ltd, PO Box 93, York YO43 3WE, United Kingdom. Electronic address:
[email protected].
(3)Fraunhofer Institute for Molecular Biology and Applied Ecology, Department of
Bioresources, Winchester Str. 2, 35394 Giessen, Germany; Institute of
Phytopathology and Applied Zoology, Justus-Liebig University of Giessen,
Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany. Electronic address:
[email protected].
Epigenetic inheritance refers to changes in gene expression that are heritable
across generations but are not caused by changes in the DNA sequence. Many
environmental factors are now known to cause epigenetic changes, including the
presence of pathogens, parasites, harmful chemicals and other stress factors.
There is increasing evidence that transcriptional reprogramming caused by
epigenetic modifications can be passed from parents to offspring. Indeed,
diseases such as cancer can occur in the offspring due to
epigenetically-inherited gene expression profiles induced by stress experienced
by the parent. Empirical studies to investigate the role of epigenetics in
trans-generational gene regulation and disease require appropriate model
organisms. In this review, we argue that selected insects can be used as models
for human diseases with an epigenetic component because the underlying molecular
mechanisms (DNA methylation, histone acetylation and the expression of
microRNAs) are evolutionarily conserved. Insects offer a number of advantages
over mammalian models including ethical acceptability, short generation times
and the potential to investigate complex interacting parameters such as
fecundity, longevity, gender ratio, and resistance to pathogens, parasites and
environmental stress.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.pbiomolbio.2015.02.009
PMID: 25778758 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31526982 | 1. Biosens Bioelectron. 2019 Nov 1;144:111695. doi: 10.1016/j.bios.2019.111695.
Epub 2019 Sep 11.
Biosensors for epigenetic biomarkers detection: A review.
Li CC(1), Wang ZY(1), Wang LJ(2), Zhang CY(3).
Author information:
(1)College of Chemistry, Chemical Engineering and Materials Science,
Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry
of Education, Shandong Provincial Key Laboratory of Clean Production of Fine
Chemicals, Shandong Normal University, Jinan, 250014, PR China.
(2)College of Chemistry, Chemical Engineering and Materials Science,
Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry
of Education, Shandong Provincial Key Laboratory of Clean Production of Fine
Chemicals, Shandong Normal University, Jinan, 250014, PR China. Electronic
address: [email protected].
(3)College of Chemistry, Chemical Engineering and Materials Science,
Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry
of Education, Shandong Provincial Key Laboratory of Clean Production of Fine
Chemicals, Shandong Normal University, Jinan, 250014, PR China. Electronic
address: [email protected].
Epigenetic inheritance is a heritable change in gene function independent of
alterations in nucleotide sequence. It regulates the normal cellular activities
of the organisms by affecting gene expression and transcription, and its
abnormal expression may lead to the developmental disorder, senile dementia, and
carcinogenesis progression. Thus, epigenetic inheritance is recognized as an
important biomarker, and the accurate quantification of epigenetic inheritance
is crucial to clinical diagnosis, drug development and cancer treatment.
Noncoding RNA, DNA methylation and histone modification are the most common
epigenetic biomarkers. The conventional biosensors (e.g., northern blotting,
radiometric, mass spectrometry and immunosorbent biosensors) for epigenetic
biomarkers assay usually suffer from hazardous radiation, complicated
manipulation, and time-consuming procedures. To facilitate the practical
applications, some new biosensors including colorimetric, luminescent, Raman
scattering spectroscopy, electrochemical and fluorescent biosensors have been
developed for the detection of epigenetic biomarkers with simplicity, rapidity,
high throughput and high sensitivity. In this review, we summarize the recent
advances in epigenetic biomarkers assay. We classify the biosensors into the
direct amplification-free and the nucleotide amplification-assisted ones, and
describe the principles of various biosensors, and further compare their
performance for epigenetic biomarkers detection. Moreover, we discuss the
emerging trends and challenges in the future development of epigenetic
biomarkers biosensors.
Copyright © 2019 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bios.2019.111695
PMID: 31526982 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32992597 | 1. Cancers (Basel). 2020 Sep 27;12(10):2773. doi: 10.3390/cancers12102773.
tRNA-Derived Small RNAs: Novel Epigenetic Regulators.
Park J(1), Ahn SH(2), Shin MG(1), Kim HK(1), Chang S(2)(3).
Author information:
(1)Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
(2)Department of Biomedical Sciences, University of Ulsan College of Medicine,
Asan Medical Center, Seoul 05505, Korea.
(3)Department of Physiology, University of Ulsan College of Medicine, Asan
Medical Center, Seoul 05505, Korea.
An epigenetic change is a heritable genetic alteration that does not involve any
nucleotide changes. While the methylation of specific DNA regions such as CpG
islands or histone modifications, including acetylation or methylation, have
been investigated in detail, the role of small RNAs in epigenetic regulation is
largely unknown. Among the many types of small RNAs, tRNA-derived small RNAs
(tsRNAs) represent a class of noncoding small RNAs with multiple roles in
diverse physiological processes, including neovascularization, sperm maturation,
immune modulation, and stress response. Regarding these roles, several
pioneering studies have revealed that dysregulated tsRNAs are associated with
human diseases, such as systemic lupus, neurological disorder, metabolic
disorder, and cancer. Moreover, recent findings suggest that tsRNAs regulate the
expression of critical genes linked with these diseases by a variety of
mechanisms, including epigenetic regulation. In this review, we will describe
different classes of tsRNAs based on their biogenesis and will focus on their
role in epigenetic regulation.
DOI: 10.3390/cancers12102773
PMCID: PMC7599909
PMID: 32992597
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/22125494 | 1. PLoS Genet. 2011 Nov;7(11):e1002372. doi: 10.1371/journal.pgen.1002372. Epub
2011 Nov 17.
Heritable epigenetic variation among maize inbreds.
Eichten SR(1), Swanson-Wagner RA, Schnable JC, Waters AJ, Hermanson PJ, Liu S,
Yeh CT, Jia Y, Gendler K, Freeling M, Schnable PS, Vaughn MW, Springer NM.
Author information:
(1)Microbial and Plant Genomics Institute, Department of Plant Biology,
University of Minnesota, Saint Paul, Minnesota, USA.
Epigenetic variation describes heritable differences that are not attributable
to changes in DNA sequence. There is the potential for pure epigenetic variation
that occurs in the absence of any genetic change or for more complex situations
that involve both genetic and epigenetic differences. Methylation of cytosine
residues provides one mechanism for the inheritance of epigenetic information. A
genome-wide profiling of DNA methylation in two different genotypes of Zea mays
(ssp. mays), an organism with a complex genome of interspersed genes and
repetitive elements, allowed the identification and characterization of examples
of natural epigenetic variation. The distribution of DNA methylation was
profiled using immunoprecipitation of methylated DNA followed by hybridization
to a high-density tiling microarray. The comparison of the DNA methylation
levels in the two genotypes, B73 and Mo17, allowed for the identification of
approximately 700 differentially methylated regions (DMRs). Several of these
DMRs occur in genomic regions that are apparently identical by descent in B73
and Mo17 suggesting that they may be examples of pure epigenetic variation. The
methylation levels of the DMRs were further studied in a panel of near-isogenic
lines to evaluate the stable inheritance of the methylation levels and to assess
the contribution of cis- and trans- acting information to natural epigenetic
variation. The majority of DMRs that occur in genomic regions without genetic
variation are controlled by cis-acting differences and exhibit relatively stable
inheritance. This study provides evidence for naturally occurring epigenetic
variation in maize, including examples of pure epigenetic variation that is not
conditioned by genetic differences. The epigenetic differences are variable
within maize populations and exhibit relatively stable trans-generational
inheritance. The detected examples of epigenetic variation, including some
without tightly linked genetic variation, may contribute to complex trait
variation.
DOI: 10.1371/journal.pgen.1002372
PMCID: PMC3219600
PMID: 22125494 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/27341739 | 1. Zoology (Jena). 2016 Aug;119(4):273-80. doi: 10.1016/j.zool.2016.05.004. Epub
2016 May 19.
The role of epigenetics in host-parasite coevolution: lessons from the model
host insects Galleria mellonella and Tribolium castaneum.
Vilcinskas A(1).
Author information:
(1)Institute for Insect Biotechnology, Justus Liebig University of Giessen,
Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany; Fraunhofer Institute for
Molecular Biology and Applied Ecology, Department of Bioresources,
Winchesterstrasse 2, D-35394 Giessen, Germany. Electronic address:
[email protected].
Recent studies addressing experimental host-parasite coevolution and
transgenerational immune priming in insects provide evidence for heritable
shifts in host resistance or parasite virulence. These rapid reciprocal
adaptations may thus be transferred to offspring generations by either genetic
changes or mechanisms that do not involve changes in the germline DNA sequence.
Epigenetic inheritance refers to changes in gene expression that are heritable
across generations and mediated by epigenetic modifications passed from parents
to offspring. Highlighting the role of epigenetics in host-parasite coevolution,
this review discusses the involvement of DNA methylation, histone
acetylation/deacetylation and microRNAs in the interactions between bacterial or
fungal parasites and model host insects such as the greater wax moth Galleria
mellonella and the red flour beetle Tribolium castaneum. These epigenetic
mechanisms are thought to participate in generation-spanning transcriptional
reprogramming in the host insect, often linking immunity with developmentally
related gene expression and contributing to the heredity of acquired
adaptations. It is proposed that the interactions during host-parasite
coevolution can therefore be expanded beyond reciprocal genetic changes to
include reciprocal epigenetic changes. Epigenetics is thus a promising and
prospering field in the context of host-parasite coevolution.
Copyright © 2016 The Author. Published by Elsevier GmbH.. All rights reserved.
DOI: 10.1016/j.zool.2016.05.004
PMID: 27341739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36057300 | 1. Int J Biol Macromol. 2022 Oct 31;219:1261-1271. doi:
10.1016/j.ijbiomac.2022.08.182. Epub 2022 Aug 31.
A review on CRISPR/Cas-based epigenetic regulation in plants.
Jogam P(1), Sandhya D(2), Alok A(3), Peddaboina V(4), Allini VR(2), Zhang B(5).
Author information:
(1)Department of Biotechnology, Kakatiya University, Warangal, Telangana 506009,
India. Electronic address: [email protected].
(2)Department of Biotechnology, Kakatiya University, Warangal, Telangana 506009,
India.
(3)Department of Plant Pathology, University of Minnesota, Saint Paul, MN 55108,
USA.
(4)Department of Microbiology, Kakatiya University, Warangal, Telangana 506009,
India.
(5)Department of Biology, East Carolina University, Greenville, NC 27858, USA.
Electronic address: [email protected].
Epigenetic changes are the heritable modifications in genes without altering DNA
sequences. The epigenetic changes occur in the plant genomes to regulate gene
expression patterns, which were used to regulate different biological processes,
including coping various environmental stresses. These changes, including DNA
methylation, non-coding RNA regulation, and histone modification, play a vital
role in the transcription and translation processes to regulate gene expression.
Gene engineering for the development of stress-tolerant crops via the DNA
methylation pathway initially needs a proper selection of genes and its
promoter. Manipulating epigenetics requires genetic engineering tools such as
Zinc finger nucleases (ZFN), transcription activator-like effector nucleases
(TALENs), and clustered regularly interspaced short palindromic repeats
(CRISPR)/CRISPR-associated protein (Cas). However, CRISPR/Cas9 mediated
epigenetic editing refers to transcriptional reprogramming at the targeted sites
using epigenetic enzymes fused with decatalytical Cas9 (dCas9). This review
focused on the different epigenetic mechanisms in plants and their potential
contribution to developing epigenetic tools. The dCas9 endonuclease tethered
with transcriptional repressor or activator domain leads to CRISPR inhibitor
(CRISPRi) or activator (CRISPRa) for regulating gene expression. The dCas9 has
been successfully fused with other various effector domains for constructing
epigenetic tools, including the DNA methyltransferase 3A (DNMT3A), or the DNA
demethylase TET. Multiple efforts have been made to improve epigenome editing in
plants. Initially, incorporating SunTag into the dCas9-EpiEffector complex was
used as an epigenetic tool; demethylation of target loci with dCas9-SunTag-TET1
futher increased its efficiency. Additionally, SunTag could also be fused with
the dCas9-DNMT3A complex to augment CpG methylation at a targeted loci.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ijbiomac.2022.08.182
PMID: 36057300 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20620207 | 1. Genomics. 2010 Oct;96(4):191-8. doi: 10.1016/j.ygeno.2010.07.001. Epub 2010
Jul 8.
Redefining regulation of DNA methylation by RNA interference.
Muthusamy V(1), Bosenberg M, Wajapeyee N.
Author information:
(1)Department of Dermatology, Yale University School of Medicine, New Haven, CT
06510, USA.
Epigenetic changes refer to heritable changes that may modulate gene expression
without affecting DNA sequence. DNA methylation is one such heritable epigenetic
change, which is causally associated with the transcription regulation of many
genes in the mammalian genome. Altered DNA methylation has been implicated in a
wide variety of human diseases including cancer. Understanding the regulation of
DNA methylation is likely to improve the ability to diagnose and treat these
diseases. With the advent of high-throughput RNA interference (RNAi) screens,
answering epigenetic questions on a genomic scale is now possible. Two recent
genome-wide RNAi screens have addressed the regulation of DNA methylation in
cancer, leading to the identification of the regulators of epigenetic silencing
by oncogenic RAS and how epigenetic silencing of the tumor suppressor RASSF1A is
maintained. These RNAi screens have much wider applications, since similar
screens can now be adapted to identify the mechanism of silencing of any human
disease-associated gene that is epigenetically regulated. In this review, we
discuss two recent genome-wide RNAi screens for epigenetic regulators and
explore potential applications in understanding DNA methylation and gene
expression regulation in mammalian cells. We also discuss some of the key
unanswered questions in the field of DNA methylation and suggest genome-wide
RNAi screens designed to answer them.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygeno.2010.07.001
PMCID: PMC3726036
PMID: 20620207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20399890 | 1. Mutat Res. 2010 Oct;705(2):83-95. doi: 10.1016/j.mrrev.2010.04.003. Epub 2010
Apr 23.
Epigenetics and chemical safety assessment.
LeBaron MJ(1), Rasoulpour RJ(1), Klapacz J(1), Ellis-Hutchings RG(1), Hollnagel
HM(2), Gollapudi BB(3).
Author information:
(1)Toxicology & Environmental Research & Consulting, The Dow Chemical Company,
1803 Building, Midland, MI 48674, USA.
(2)Toxicology & Environmental Research & Consulting, The Dow Chemical Company,
Horgen, Switzerland.
(3)Toxicology & Environmental Research & Consulting, The Dow Chemical Company,
1803 Building, Midland, MI 48674, USA. Electronic address: [email protected].
Epigenetics, as it pertains to biology and toxicology, can be defined as
heritable changes in gene expression that do not involve mutations and are
propagated without continued stimulus. Although potentially reversible, these
heritable changes may be classified as mitotic, meiotic, or transgenerational,
implicating the wide-ranging impact of epigenetic control in cellular function.
A number of biological responses have been classified as being caused by an
"epigenetic alteration," sometimes based on sound scientific evidence and often
in lieu of an identified genetic mutation. Complicating the understanding and
interpretation of perceived epigenetic alterations is an incomplete
understanding of the normal state and dynamic variation of the epigenome, which
can differ widely between cell and tissue types and stage of development or age.
This emerging field is likely to have a profound impact on the study and
practice of toxicology in coming years. This document reviews the current state
of the science in epigenetic modifications, techniques used to measure these
changes, and evaluates the current toxicology testing battery with respect to
strengths and potential weaknesses in the identification of epigenetics changes.
In addition, case studies implicating transgenerational effects induced by
diethylstilbestrol, vinclozolin, and bisphenol A were reviewed to illustrate the
application of epigenetics in safety assessment and the strengths and
limitations of the study designs. An assessment of toxicology tests currently
used in safety evaluation revealed that these tests are expected to identify any
potential adverse outcomes resulting from epigenetic changes. Furthermore, in
order to increase our understanding of the science of epigenetics in toxicology,
this review has revealed that a solid understanding of the biology and variation
in the epigenome is essential to contextualize concerns about possible adverse
health effects related to epigenetic changes. Finally, the fundamental
principles guiding toxicology studies, including relevant doses, dose-rates,
routes of exposure, and experimental models, need to be taken into consideration
in the design and interpretation of studies within this emerging area of
science.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.mrrev.2010.04.003
PMID: 20399890 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17413847 | 1. Pediatr Res. 2007 May;61(5 Pt 2):30R-37R. doi: 10.1203/pdr.0b013e31804575f7.
Metastable epialleles, imprinting, and the fetal origins of adult diseases.
Dolinoy DC(1), Das R, Weidman JR, Jirtle RL.
Author information:
(1)Department of Radiation Oncology, University Program in Genetics and
Genomics, Duke University Medical Center, Durham, NC 27710, USA.
Epigenetics is the study of the heritable changes in gene expression that occur
without a change in the DNA sequence itself. These heritable epigenetic changes
include chromatin folding and attachment to the nuclear matrix, packaging of DNA
around nucleosomes, histone modifications, and DNA methylation. The epigenome is
particularly susceptible to dysregulation during gestation, neonatal
development, puberty, and old age. Nevertheless, it is most vulnerable to
environmental factors during embryogenesis because the DNA synthetic rate is
high, and the elaborate DNA methylation patterning and chromatin structure
required for normal tissue development is established during early development.
Metastable epialleles are alleles that are variably expressed in genetically
identical individuals due to epigenetic modifications established during early
development and are thought to be particularly vulnerable to environmental
influences. The viable yellow agouti (A(vy)) allele, whose expression is
correlated to DNA methylation, is a murine metastable epiallele, which has been
used as an epigenetic biosensor for environmental factors affecting the fetal
epigenome. In this review, we introduce epigenetic gene regulation, describe
important epigenetic phenomenon in mammals, summarize literature linking the
early environment to developmental plasticity of the fetal epigenome, and
promote the necessity to identify epigenetically labile genes in the mouse and
human genomes.
DOI: 10.1203/pdr.0b013e31804575f7
PMID: 17413847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19416939 | 1. Genetics. 2009 Jul;182(3):845-50. doi: 10.1534/genetics.109.102798. Epub 2009
May 4.
Epigenetic inheritance and the missing heritability problem.
Slatkin M(1).
Author information:
(1)Department of Integrative Biology, University of California, Berkeley,
California 94720-3140, USA. [email protected]
Comment in
Genetics. 2009 Aug;182(4):1397-8. doi: 10.1534/genetics.109.106146.
Epigenetic phenomena, and in particular heritable epigenetic changes, or
transgenerational effects, are the subject of much discussion in the current
literature. This article presents a model of transgenerational epigenetic
inheritance and explores the effect of epigenetic inheritance on the risk and
recurrence risk of a complex disease. The model assumes that epigenetic
modifications of the genome are gained and lost at specified rates and that each
modification contributes multiplicatively to disease risk. The potentially high
rate of loss of epigenetic modifications causes the probability of identity in
state in close relatives to be smaller than is implied by their relatedness. As
a consequence, the recurrence risk to close relatives is reduced. Although
epigenetic modifications may contribute substantially to average risk, they will
not contribute much to recurrence risk and heritability unless they persist on
average for many generations. If they do persist for long times, they are
equivalent to mutations and hence are likely to be in linkage disequilibrium
with SNPs surveyed in genomewide association studies. Thus epigenetic
modifications are a potential solution to the problem of missing causality of
complex diseases but not to the problem of missing heritability. The model
highlights the need for empirical estimates of the persistence times of
heritable epialleles.
DOI: 10.1534/genetics.109.102798
PMCID: PMC2710163
PMID: 19416939 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20599773 | 1. Biochem Pharmacol. 2010 Dec 15;80(12):1771-92. doi: 10.1016/j.bcp.2010.06.036.
Epub 2010 Jun 26.
Cancer chemoprevention by dietary polyphenols: promising role for epigenetics.
Link A(1), Balaguer F, Goel A.
Author information:
(1)Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology,
Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University
Medical Center, Dallas, TX 75246, USA.
Epigenetics refers to heritable changes that are not encoded in the DNA sequence
itself, but play an important role in the control of gene expression. In
mammals, epigenetic mechanisms include changes in DNA methylation, histone
modifications and non-coding RNAs. Although epigenetic changes are heritable in
somatic cells, these modifications are also potentially reversible, which makes
them attractive and promising avenues for tailoring cancer preventive and
therapeutic strategies. Burgeoning evidence in the last decade has provided
unprecedented clues that diet and environmental factors directly influence
epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric,
soybeans, broccoli and others have shown to possess multiple cell-regulatory
activities within cancer cells. More recently, we have begun to understand that
some of the dietary polyphenols may exert their chemopreventive effects in part
by modulating various components of the epigenetic machinery in humans. In this
article, we first discuss the contribution of diet and environmental factors on
epigenetic alterations; subsequently, we provide a comprehensive review of
literature on the role of various dietary polyphenols. In particular, we
summarize the current knowledge on a large number of dietary agents and their
effects on DNA methylation, histone modifications and regulation of expression
of the non-coding miRNAs in various in vitro and in vivo models. We emphasize
how increased understanding of the chemopreventive effects of dietary
polyphenols on specific epigenetic alterations may provide unique and yet
unexplored novel and highly effective chemopreventive strategies for reducing
the health burden of cancer and other diseases in humans.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bcp.2010.06.036
PMCID: PMC2974019
PMID: 20599773 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures: None of the authors have any
potential conflicts to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/22567405 | 1. Genet Res Int. 2012;2012:867951. doi: 10.1155/2012/867951. Epub 2011 Nov 29.
Genetics: polymorphisms, epigenetics, and something in between.
Maggert KA(1).
Author information:
(1)Department of Biology, Texas A&M University, College Station, TX 77843, USA.
At its broadest sense, to say that a phenotype is epigenetic suggests that it
occurs without changes in DNA sequence, yet is heritable through cell division
and occasionally from one organismal generation to the next. Since gene
regulatory changes are oftentimes in response to environmental stimuli and may
be retained in descendent cells, there is a growing expectation that one's
experiences may have consequence for subsequent generations and thus impact
evolution by decoupling a selectable phenotype from its underlying heritable
genotype. But the risk of this overbroad use of "epigenetic" is a conflation of
genuine cases of heritable non-sequence genetic information with trivial modes
of gene regulation. A look at the term "epigenetic" and some problems with its
increasing prevalence argues for a more reserved and precise set of defining
characteristics. Additionally, questions arising about how we define the
"sequence independence" aspect of epigenetic inheritance suggest a form of
genome evolution resulting from induced polymorphisms at repeated loci (e.g.,
the rDNA or heterochromatin).
DOI: 10.1155/2012/867951
PMCID: PMC3335516
PMID: 22567405 |
http://www.ncbi.nlm.nih.gov/pubmed/17413852 | 1. Pediatr Res. 2007 May;61(5 Pt 2):24R-29R. doi: 10.1203/pdr.0b013e3180457684.
Epigenetics and microRNAs.
Chuang JC(1), Jones PA.
Author information:
(1)Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive
Cancer Center, University of Southern California, Los Angeles 90089, USA.
Epigenetics is defined as mitotically and meiotically heritable changes in gene
expression that do not involve a change in the DNA sequence. Two major areas of
epigenetics-DNA methylation and histone modifications-are known to have profound
effects on controlling gene expression. DNA methylation is involved in normal
cellular control of expression, and aberrant hypermethylation can lead to
silencing of tumor-suppressor genes in carcinogenesis. Histone modifications
control the accessibility of the chromatin and transcriptional activities inside
a cell. MicroRNAs (miRNAs) are small RNA molecules, approximately 22 nucleotides
long that can negatively control their target gene expression
posttranscriptionally. There are currently more than 460 human miRNAs known, and
the total number is predicted to be much larger. Recently, the expression of
miRNAs has been definitively linked to cancer development, and miRNA profiles
can be used to classify human cancers. miRNAs are encoded in our genome and are
generally transcribed by RNA polymerase II. Despite the growing evidence for
their importance in normal physiology, little is known about the regulation of
miRNA expression. In this review, we will examine the relationship between
miRNAs and epigenetics. We examine the effects of miRNAs on epigenetic
machinery, and the control of miRNA expression by epigenetic mechanisms.
Epigenetics is defined as heritable changes in gene expression that do not
involve a change in DNA sequence.
DOI: 10.1203/pdr.0b013e3180457684
PMID: 17413852 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33866814 | 1. Philos Trans R Soc Lond B Biol Sci. 2021 Jun 7;376(1826):20200111. doi:
10.1098/rstb.2020.0111. Epub 2021 Apr 19.
How does epigenetics influence the course of evolution?
Ashe A(1), Colot V(2), Oldroyd BP(3).
Author information:
(1)School of Life and Environmental Sciences, University of Sydney, Sydney, New
South Wales 2006, Australia.
(2)Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Centre National
de la Recherche Scientifique (CNRS), Institut National de la Santé et de la
Recherche Médicale (INSERM), Ecole Normale Supérieure, PSL Research University,
75005 Paris, France.
(3)Wissenschaftskolleg zu Berlin, Wallotstrasse 19, 14193 Berlin, Germany.
Epigenetics is the study of changes in gene activity that can be transmitted
through cell divisions but cannot be explained by changes in the DNA sequence.
Epigenetic mechanisms are central to gene regulation, phenotypic plasticity,
development and the preservation of genome integrity. Epigenetic mechanisms are
often held to make a minor contribution to evolutionary change because
epigenetic states are typically erased and reset at every generation, and are
therefore, not heritable. Nonetheless, there is growing appreciation that
epigenetic variation makes direct and indirect contributions to evolutionary
processes. First, some epigenetic states are transmitted intergenerationally and
affect the phenotype of offspring. Moreover, bona fide heritable 'epialleles'
exist and are quite common in plants. Such epialleles could, therefore, be
subject to natural selection in the same way as conventional DNA sequence-based
alleles. Second, epigenetic variation enhances phenotypic plasticity and
phenotypic variance and thus can modulate the effect of natural selection on
sequence-based genetic variation. Third, given that phenotypic plasticity is
central to the adaptability of organisms, epigenetic mechanisms that generate
plasticity and acclimation are important to consider in evolutionary theory.
Fourth, some genes are under selection to be 'imprinted' identifying the sex of
the parent from which they were derived, leading to parent-of-origin-dependent
gene expression and effects. These effects can generate hybrid disfunction and
contribute to speciation. Finally, epigenetic processes, particularly DNA
methylation, contribute directly to DNA sequence evolution, because they act as
mutagens on the one hand and modulate genome stability on the other by keeping
transposable elements in check. This article is part of the theme issue 'How
does epigenetics influence the course of evolution?'
DOI: 10.1098/rstb.2020.0111
PMCID: PMC8059608
PMID: 33866814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23580343 | 1. Bioessays. 2013 Jun;35(6):571-8. doi: 10.1002/bies.201200169. Epub 2013 Apr
12.
How epigenetic mutations can affect genetic evolution: model and mechanism.
Klironomos FD(1), Berg J, Collins S.
Author information:
(1)Institute for Theoretical Physics, University of Cologne, Cologne, Germany.
We hypothesize that heritable epigenetic changes can affect rates of fitness
increase as well as patterns of genotypic and phenotypic change during
adaptation. In particular, we suggest that when natural selection acts on pure
epigenetic variation in addition to genetic variation, populations adapt faster,
and adaptive phenotypes can arise before any genetic changes. This may make it
difficult to reconcile the timing of adaptive events detected using conventional
population genetics tools based on DNA sequence data with environmental drivers
of adaptation, such as changes in climate. Epigenetic modifications are
frequently associated with somatic cell differentiation, but recently epigenetic
changes have been found that can be transmitted over many generations. Here, we
show how the interplay of these heritable epigenetic changes with genetic
changes can affect adaptive evolution, and how epigenetic changes affect the
signature of selection in the genetic record.
© 2013 WILEY Periodicals, Inc.
DOI: 10.1002/bies.201200169
PMID: 23580343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18042143 | 1. APMIS. 2007 Oct;115(10):1039-59. doi: 10.1111/j.1600-0463.2007.apm_636.xml.x.
Epigenetic changes in cancer.
Grønbaek K(1), Hother C, Jones PA.
Author information:
(1)Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
[email protected]
A cancer develops when a cell acquires specific growth advantages through the
stepwise accumulation of heritable changes in gene function. Basically, this
process is directed by changes in two different classes of genes: Tumor
suppressor genes that inhibit cell growth and survival and oncogenes that
promote cell growth and survival. Since several alterations are usually required
for a cancer to fully develop, the malignant phenotype is determined by the
compound status of tumor suppressor genes and oncogenes. Cancer genes may be
changed by several mechanisms, which potentially alter the protein encoding
nucleotide template, change the copy number of genes, or lead to increased gene
transcription. Epigenetic alterations, which, by definition, comprise
mitotically and meiotically heritable changes in gene expression that are not
caused by changes in the primary DNA sequence, are increasingly being recognized
for their roles in carcinogenesis. These epigenetic alterations may involve
covalent modifications of amino acid residues in the histones around which the
DNA is wrapped, and changes in the methylation status of cytosine bases (C) in
the context of CpG dinucleotides within the DNA itself. Methylation of clusters
of CpGs called "CpG-islands" in the promoters of genes has been associated with
heritable gene silencing. The present review will focus on how disruption of the
epigenome can contribute to cancer. In contrast to genetic alterations, gene
silencing by epigenetic modifications is potentially reversible. Treatment by
agents that inhibit cytosine methylation and histone deacetylation can initiate
chromatin decondensation, demethylation and reestablishment of gene
transcription. Accordingly, in the clinical setting, DNA methylation and histone
modifications are very attractive targets for the development and implementation
of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic
therapy has recently been approved by the United States Food and Drug
Administration (US FDA) for use in the treatment of myelodysplastic syndrome
(MDS) and primary cutaneous T-cell lymphoma (CTCL).
DOI: 10.1111/j.1600-0463.2007.apm_636.xml.x
PMID: 18042143 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22975443 | 1. Prog Biophys Mol Biol. 2013 Apr;111(2-3):99-107. doi:
10.1016/j.pbiomolbio.2012.08.014. Epub 2012 Sep 4.
Epigenetic inheritance and plasticity: The responsive germline.
Jablonka E(1).
Author information:
(1)Cohn Institute for the History and Philosophy of Science and Ideas, Tel Aviv
University, Tel Aviv 69978, Israel. [email protected]
Developmental plasticity, the capacity of a single genotype to give rise to
different phenotypes, affects evolutionary dynamics by influencing the rate and
direction of phenotypic change. It is based on regulatory changes in gene
expression and gene products, which are partially controlled by epigenetic
mechanisms. Plasticity involves not just epigenetic changes in somatic cells and
tissues; it can also involve changes in germline cells. Germline epigenetic
plasticity increases evolvability, the capacity to generate heritable,
selectable, phenotypic variations, including variations that lead to novel
functions. I discuss studies that show that some complex adaptive responses to
new challenges are mediated by germline epigenetic processes, which can be
transmitted over variable number of generations, and argue that the heritable
variations that are generated epigenetically have an impact on both small-scale
and large-scale aspects of evolution. First, I review some recent ecological
studies and models that show that germline (gametic) epigenetic inheritance can
lead to cumulative micro-evolutionary changes that are rapid and
semi-directional. I suggest that "priming" and "epigenetic learning" may be of
special importance in generating heritable, fine-tuned adaptive responses in
populations. Second, I consider work showing how genomic and environmental
stresses can also lead to epigenome repatterning, and produce changes that are
saltational.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.pbiomolbio.2012.08.014
PMID: 22975443 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18331347 | 1. FEBS J. 2008 Apr;275(8):1617-23. doi: 10.1111/j.1742-4658.2008.06330.x. Epub
2008 Mar 7.
Epigenetics: differential DNA methylation in mammalian somatic tissues.
Nagase H(1), Ghosh S.
Author information:
(1)Advanced Research Institute for the Sciences and Humanities, Nihon
University, 12-5 Goban-cho, Chiyoda-ku, Tokyo, Japan.
[email protected]
Epigenetics refers to heritable phenotypic alterations in the absence of DNA
sequence changes, and DNA methylation is one of the extensively studied
epigenetic alterations. DNA methylation is an evolutionally conserved mechanism
to regulate gene expression in mammals. Because DNA methylation is preserved
during DNA replication it can be inherited. Thus, DNA methylation could be a
major mechanism by which to produce semi-stable changes in gene expression in
somatic tissues. Although it remains controversial whether germ-line DNA
methylation in mammalian genomes is stably heritable, frequent tissue-specific
and disease-specific de novo methylation events are observed during somatic cell
development/differentiation. In this minireview, we discuss the use of
restriction landmark genomic scanning, together with in silico analysis, to
identify differentially methylated regions in the mammalian genome. We then
present a rough overview of quantitative DNA methylation patterns at 4600 NotI
sites and more than 150 differentially methylated regions in several C57BL/6J
mouse tissues. Comparative analysis between mice and humans suggests that some,
but not all, tissue-specific differentially methylated regions are conserved. A
deeper understanding of cell-type-specific differences in DNA methylation might
lead to a better illustration of the mechanisms behind tissue-specific
differentiation in mammals.
DOI: 10.1111/j.1742-4658.2008.06330.x
PMID: 18331347 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34493403 | 1. Trends Genet. 2022 Feb;38(2):116-119. doi: 10.1016/j.tig.2021.08.011. Epub
2021 Sep 4.
Heritable epigenetic changes at single genes: challenges and opportunities in
Caenorhabditis elegans.
Chey M(1), Jose AM(2).
Author information:
(1)Department of Cell Biology and Molecular Genetics, University of Maryland,
College Park, MD 20742, USA.
(2)Department of Cell Biology and Molecular Genetics, University of Maryland,
College Park, MD 20742, USA. Electronic address: [email protected].
Organisms rely on stereotyped patterns of gene expression for similar form and
function in every generation. The analysis of epigenetic changes in the
expression of different genes across generations can provide the rationale for
measured actions in one generation that consider impact on future generations.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tig.2021.08.011
PMCID: PMC9436772
PMID: 34493403 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests No interests are
declared. |
http://www.ncbi.nlm.nih.gov/pubmed/25191382 | 1. Tanaffos. 2011;10(4):7-16.
Epigenetics and chromatin remodeling play a role in lung disease.
Mortaz E(1), Masjedi MR(2), Barnes PJ(3), Adcock IM(3).
Author information:
(1)Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences,
Faculty of Science, Utrecht University, Utrecht, The Netherlands ; Chronic
Respiratory Disease Research Center, National Research Institute of Tuberculosis
and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences,
Tehran, Iran.
(2)Chronic Respiratory Disease Research Center, National Research Institute of
Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
(3)Cell and Molecular Biology Group, Airways Disease Section, National Heart and
Lung Institute, Imperial College London, London, UK.
Epigenetics is defined as heritable changes that affect gene expression without
altering the DNA sequence. Epigenetic regulation of gene expression is
facilitated through different mechanisms such as DNA methylation, histone
modifications and RNA-associated silencing by small non-coding RNAs. All these
mechanisms are crucial for normal development, differentiation and
tissue-specific gene expression. These three systems interact and stabilize one
another and can initiate and sustain epigenetic silencing, thus determining
heritable changes in gene expression. Histone acetylation regulates diverse
cellular functions including inflammatory gene expression, DNA repair and cell
proliferation. Transcriptional coactivators possess intrinsic histone
acetyltransferase activity and this activity drives inflammatory gene
expression. Eleven classical histone deacetylases (HDACs) act to regulate the
expression of distinct subsets of inflammatory/immune genes. Thus, loss of HDAC
activity or the presence of HDAC inhibitors can further enhance inflammatory
gene expression by producing a gene-specific change in HAT activity. For
example, HDAC2 expression and activity are reduced in lung macrophages, biopsy
specimens, and blood cells from patients with severe asthma and smoking
asthmatics, as well as in patients with chronic obstructive pulmonary disease
(COPD). This may account, at least in part, for the enhanced inflammation and
reduced steroid responsiveness seen in these patients. Other proteins,
particularly transcription factors, are also acetylated and are targets for
deacetylation by HDACs and sirtuins, a related family of 7 predominantly protein
deacetylases. Thus the acetylation/deacetylation status of NF-κB and the
glucocorticoid receptor can also affect the overall expression pattern of
inflammatory genes and regulate the inflammatory response. Understanding and
targeting specific enzymes involved in this process might lead to new
therapeutic agents, particularly in situations in which current
anti-inflammatory therapies are suboptimal.
PMCID: PMC4153170
PMID: 25191382 |
http://www.ncbi.nlm.nih.gov/pubmed/25104823 | 1. EMBO J. 2014 Sep 17;33(18):1987-98. doi: 10.15252/embj.201488883. Epub 2014
Aug 7.
Epigenetic memory in plants.
Iwasaki M(1), Paszkowski J(1).
Author information:
(1)The Sainsbury Laboratory, University of Cambridge, Cambridge, UK
[email protected] [email protected].
Epigenetics refers to heritable changes in patterns of gene expression that
occur without alterations in DNA sequence. The epigenetic mechanisms involve
covalent modifications of DNA and histones, which affect transcriptional
activity of chromatin. Since chromatin states can be propagated through mitotic
and meiotic divisions, epigenetic mechanisms are thought to provide heritable
'cellular memory'. Here, we review selected examples of epigenetic memory in
plants and briefly discuss underlying mechanisms.
© 2014 The Authors.
DOI: 10.15252/embj.201488883
PMCID: PMC4195768
PMID: 25104823 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27591071 | 1. Gen Comp Endocrinol. 2017 May 1;245:122-126. doi: 10.1016/j.ygcen.2016.08.010.
Epub 2016 Aug 30.
Effects of BPA on female reproductive function: The involvement of epigenetic
mechanism.
Santangeli S(1), Maradonna F(1), Olivotto I(2), Piccinetti CC(2), Gioacchini
G(2), Carnevali O(3).
Author information:
(1)Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle
Marche, Via Brecce Bianche, 60131 Ancona, Italy; INBB Consorzio
Interuniversitario di Biosistemi e Biostrutture, 00136 Roma, Italy.
(2)Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle
Marche, Via Brecce Bianche, 60131 Ancona, Italy.
(3)Dipartimento Scienze della Vita e dell'Ambiente, Università Politecnica delle
Marche, Via Brecce Bianche, 60131 Ancona, Italy; INBB Consorzio
Interuniversitario di Biosistemi e Biostrutture, 00136 Roma, Italy. Electronic
address: [email protected].
Epigenetic modifications are classified as heritable and reversible chemical
modifications of chromatin that do not cause changes in DNA sequence. Changes in
epigenetic modifications can be caused by exposure to certain environmental
factors, such as contaminants like bisphenol A (BPA). Bisphenol A is ubiquitous
in the environment and produced in large quantities, and known to have
hormone-like activity, whereby disrupting endocrine function. Because of
evidence for disruption of sex steroid mediated pathways, there is a concern
that BPA could have adverse effects on female reproduction. The purpose of this
review is to summarize the effects of BPA on adult female reproduction with
focus on epigenetic changes that can be heritable.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ygcen.2016.08.010
PMID: 27591071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30963999 | 1. Elife. 2019 Apr 9;8:e39380. doi: 10.7554/eLife.39380.
Intergenerational epigenetic inheritance of cancer susceptibility in mammals.
Lesch BJ(1), Tothova Z(2)(3), Morgan EA(4), Liao Z(5)(6), Bronson RT(7), Ebert
BL(2)(3), Page DC(1)(8)(9).
Author information:
(1)Whitehead Institute, Cambridge, United States.
(2)Department of Medicine, Division of Hematology, Brigham and Women's Hospital,
Harvard Medical School, Boston, United States.
(3)Broad Institute of MIT and Harvard, Cambridge, United States.
(4)Department of Pathology, Brigham and Women's Hospital, Harvard Medical
School, Boston, United States.
(5)Department of Genetics, Yale School of Medicine, New Haven, United States.
(6)Yale Cancer Center, Yale School of Medicine, New Haven, United States.
(7)Department of Pathology, Tufts University School of Medicine and Veterinary
Medicine, North Grafton, United States.
(8)Department of Biology, Massachusetts Institute of Technology, Cambridge,
United States.
(9)Howard Hughes Medical Institute, Whitehead Institute, Cambridge, United
States.
Susceptibility to cancer is heritable, but much of this heritability remains
unexplained. Some 'missing' heritability may be mediated by epigenetic changes
in the parental germ line that do not involve transmission of genetic variants
from parent to offspring. We report that deletion of the chromatin regulator
Kdm6a (Utx) in the paternal germ line results in elevated tumor incidence in
genetically wild type mice. This effect increases following passage through two
successive generations of Kdm6a male germline deletion, but is lost following
passage through a wild type germ line. The H3K27me3 mark is redistributed in
sperm of Kdm6a mutants, and we define approximately 200 H3K27me3-marked regions
that exhibit increased DNA methylation, both in sperm of Kdm6a mutants and in
somatic tissue of progeny. Hypermethylated regions in enhancers may alter
regulation of genes involved in cancer initiation or progression. Epigenetic
changes in male gametes may therefore impact cancer susceptibility in adult
offspring.
© 2019, Lesch et al.
DOI: 10.7554/eLife.39380
PMCID: PMC6456297
PMID: 30963999 [Indexed for MEDLINE]
Conflict of interest statement: BL, ZT, EM, ZL, RB, BE, DP No competing
interests declared |
http://www.ncbi.nlm.nih.gov/pubmed/20416204 | 1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Apr;18(2):531-5.
[Epigenetic alterations in myelodysplastic syndromes].
[Article in Chinese]
Xu F(1), Li X.
Author information:
(1)Department of Hematology, The Sixth People's Hospital, Shanghai Jiaotong
University, Shanghai 200233, China.
Epigenetic alterations are defined as heritable changes in gene expression
mediated through mechanisms other than alterations in the DNA sequence itself,
including DNA promoter methylation and various histone covalent modifications.
Interacting of numerous epigenetic-associated molecules results in histone
deacetylation/methylation and promoter methylation of suppressor genes, thereby
transcription factors don't bind with promoters, leading to deactivation of
tumor suppressor genes. It is widely accepted that epigenetic alterations play
an important role in cancer development. It have known that many epigenetic
alterations exist in myelodysplastic syndromes, for instance, promoter
methylation of key control gene and aberrance of PcG, which probably have
critical contribution to progression and prognosis of myelodysplastic syndromes.
In future, it will be promising that epigenetic alterations serve as biomarkers
for detection, evaluation of disease status and assessment of prognosis.
Molecular basis of epigenetic alterations, inactivation of suppressor genes and
abnormal expression of PcG in MDS are reviewed in this article.
PMID: 20416204 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33767749 | 1. Evol Appl. 2020 Nov 25;14(3):746-757. doi: 10.1111/eva.13153. eCollection 2021
Mar.
Insecticide exposure affects intergenerational patterns of DNA methylation in
the Colorado potato beetle, Leptinotarsa decemlineata.
Brevik K(1), Bueno EM(1), McKay S(2), Schoville SD(3), Chen YH(1).
Author information:
(1)Department of Plant and Soil Science University of Vermont Burlington VT USA.
(2)Department of Animal and Veterinary Sciences University of Vermont Burlington
VT USA.
(3)Department of Entomology University of Wisconsin Madison WI USA.
Insecticide use is pervasive as a selective force in modern agroecosystems.
Insect herbivores exposed to these insecticides have been able to rapidly evolve
resistance to them, but how they are able to do so is poorly understood. One
possible but largely unexplored explanation is that exposure to sublethal doses
of insecticides may alter epigenetic patterns that are heritable. For instance,
epigenetic mechanisms, such as DNA methylation that modifies gene expression
without changing the underlying genetic code, may facilitate the emergence of
resistant phenotypes in complex ways. We assessed the effects of sublethal
insecticide exposure, with the neonicotinoid imidacloprid, on DNA methylation in
the Colorado potato beetle, Leptinotarsa decemlineata, examining both global
changes in DNA methylation and specific changes found within genes and
transposable elements. We found that exposure to insecticide led to decreases in
global DNA methylation for parent and F2 generations and that many of the sites
of changes in methylation are found within genes associated with insecticide
resistance, such as cytochrome P450s, or within transposable elements. Exposure
to sublethal doses of insecticide caused heritable changes in DNA methylation in
an agricultural insect herbivore. Therefore, epigenetics may play a role in
insecticide resistance, highlighting a fundamental mechanism of evolution while
informing how we might better coexist with insect species in agroecosystems.
© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons
Ltd.
DOI: 10.1111/eva.13153
PMCID: PMC7980262
PMID: 33767749
Conflict of interest statement: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/24678826 | 1. Epigenetics Chromatin. 2014 Mar 29;7(1):6. doi: 10.1186/1756-8935-7-6.
Transgenerational epigenetics in the germline cycle of Caenorhabditis elegans.
Kelly WG(1).
Author information:
(1)Biology Department, Emory University, Atlanta, GA 30322, USA.
[email protected].
Epigenetic mechanisms create variably stable changes in gene expression through
the establishment of heritable states of chromatin architecture. While many
epigenetic phenomena are, by definition, heritably passed through cell division
during animal and plant development, evidence suggests that 'epigenetic states'
may also be inherited across multiple generations. Work in the nematode
Caenorhabditis elegans has uncovered a number of mechanisms that participate in
regulating the transgenerational passage of epigenetic states. These mechanisms
include some that establish and maintain heritable epigenetic information in the
form of histone modifications, as well as those that filter the epigenetic
information that is stably transmitted. The information appears to influence and
help guide or regulate gene activity and repression in subsequent generations.
Genome surveillance mechanisms guided by small RNAs appear to be involved in
identifying and directing heritable repression of genomic elements, and thus may
participate in filtering information that is inappropriate for stable
transmission. This review will attempt to summarize recent findings that
illustrate this simple nematode to be a truly elegant resource for defining
emerging biological paradigms.As the cell lineage that links generations, the
germline is the carrier of both genetic and epigenetic information. Like genetic
information, information in the epigenome can heritably affect gene regulation
and phenotype; yet unlike genetic information, the epigenome of the germ lineage
is highly modified within each generation. Despite such alterations, some
epigenetic information is highly stable across generations, leading to
transgenerationally stable phenotypes that are unlinked to genetic changes.
Studies in the nematode C. elegans have uncovered mechanisms that contribute to
transgenerational repression as well as to the expression of genes that rely on
histone modifying machinery and/or non-coding RNA-based mechanisms. These
studies indicate that epigenetic mechanisms operating within the germ cell cycle
of this organism filter and maintain an epigenetic memory that is required for
germ cell function and can also influence gene expression in somatic lineages.
DOI: 10.1186/1756-8935-7-6
PMCID: PMC3973826
PMID: 24678826 |
http://www.ncbi.nlm.nih.gov/pubmed/31431820 | 1. Ther Adv Hematol. 2019 Aug 6;10:2040620719866081. doi:
10.1177/2040620719866081. eCollection 2019.
Insights into novel emerging epigenetic drugs in myeloid malignancies.
Chandhok NS(1), Prebet T(2).
Author information:
(1)Division of Hematology/Oncology, Smilow Cancer Center at Yale New Haven
Hospital, New Haven, CT, USA.
(2)Division of Hematology/Oncology, Smilow Cancer Center at Yale New Haven
Hospital, 35 Park Street, New Haven, CT 06511, USA.
Epigenetics has been defined as 'a stably heritable phenotype resulting from
changes in a chromosome without alterations in the DNA sequence' and several
epigenetic regulators are recurrently mutated in hematological malignancies.
Epigenetic modifications include changes such as DNA methylation, histone
modifications and RNA associated gene silencing. Transcriptional regulation,
chromosome stability, DNA replication and DNA repair are all controlled by these
modifications. Mutations in genes encoding epigenetic modifiers are a frequent
occurrence in hematologic malignancies and important in both the initiation and
progression of cancer. Epigenetic modifications are also frequently reversible,
allowing excellent opportunities for therapeutic intervention. The goal of
epigenetic therapies is to reverse epigenetic dysregulation, restore the
epigenetic balance, and revert malignant cells to a more normal condition. The
role of epigenetic therapies thus far is most established in hematologic
malignancies, with several agents already approved by the US Food and Drug
Administration. In this review, we discuss pharmacological agents targeting
epigenetic regulators.
DOI: 10.1177/2040620719866081
PMCID: PMC6685116
PMID: 31431820
Conflict of interest statement: Conflict of interest statement: The authors
declare that there is no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/17684399 | 1. Forum Nutr. 2007;60:31-41. doi: 10.1159/000107065.
Epigenomics and nutrition.
Cobiac L(1).
Author information:
(1)Preventative Health National Research Flagship, CSIRO, Adelaide, Australia.
Epigenomics or epigenetics refers to the modification of DNA that can influence
the phenotype through changing gene expression without altering the nucleotide
sequence of the DNA. Two examples are methylation of DNA and acetylation of the
histone DNA-binding proteins. Dietary components - both nutrients and
nonnutrients - can influence these epigenetic events, altering genetic
expression and potentially modifying disease risk. Some of these epigenetic
changes appear to be heritable. Understanding the role that diet and nutrition
play in modifying genetic expression is complex given the range of food choices,
the diversity of nutrient intakes, the individual differences in genetic
backgrounds and intestinal physiological environments where food is metabolized,
as well as the impact on and acceptance of new technologies by consumers.
DOI: 10.1159/000107065
PMID: 17684399 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22419988 | 1. Interface Focus. 2012 Feb 6;2(1):42-8. doi: 10.1098/rsfs.2011.0070. Epub 2011
Sep 14.
The epigenome and top-down causation.
Davies PC(1).
Author information:
(1)The Beyond Center for Fundamental Concepts in Science , Arizona State
University , Tempe, AZ , USA.
Genes store heritable information, but actual gene expression often depends on
many so-called epigenetic factors, both physical and chemical, external to DNA.
Epigenetic changes can be both reversible and heritable. The genome is
associated with a physical object (DNA) with a specific location, whereas the
epigenome is a global, systemic, entity. Furthermore, genomic information is
tied to specific coded molecular sequences stored in DNA. Although epigenomic
information can be associated with certain non-DNA molecular sequences, it is
mostly not. Therefore, there does not seem to be a stored 'epigenetic programme'
in the information-theoretic sense. Instead, epigenomic control is-to a large
extent-an emergent self-organizing phenomenon, and the real-time operation of
the epigenetic 'project' lies in the realm of nonlinear bifurcations,
interlocking feedback loops, distributed networks, top-down causation and other
concepts familiar from the complex systems theory. Lying at the heart of vital
eukaryotic processes are chromatin structure, organization and dynamics.
Epigenetics provides striking examples of how bottom-up genetic and top-down
epigenetic causation intermingle. The fundamental question then arises of how
causal efficacy should be attributed to biological information. A proposal is
made to implement explicit downward causation by coupling information directly
to the dynamics of chromatin, thus permitting the coevolution of dynamical laws
and states, and opening up a new sector of dynamical systems theory that
promises to display rich self-organizing and self-complexifying behaviour.
DOI: 10.1098/rsfs.2011.0070
PMCID: PMC3262298
PMID: 22419988 |
http://www.ncbi.nlm.nih.gov/pubmed/10479537 | 1. J Theor Biol. 1999 Sep 7;200(1):19-37. doi: 10.1006/jtbi.1999.0974.
Epigenetic inheritance, genetic assimilation and speciation.
Pál C(1), Miklós I.
Author information:
(1)Department of Plant Taxonomy and Ecology, Loránd Eötvös University, Budapest,
Ludovika 2, H-1083, Hungary. [email protected]
Epigenetic inheritance systems enable the environmentally induced phenotypes to
be transmitted between generations. Jablonka and Lamb (1991, 1995) proposed that
these systems have a substantial role during speciation. They argued that
divergence of isolated populations may be first triggered by the accumulation of
(heritable) phenotypic differences that are later followed and strengthened by
genetic changes. The plausibility of this idea is examined in this paper. At
first, we discuss the "exploratory" behaviour of an epigenetic inheritance
system on a one peak adaptive landscape. If a quantitative trait is far from the
optimum, then it is advantageous to induce heritable phenotypic variation.
Conversely, if the genotypes get closer to the peak, it is more favorable to
canalize the phenotypic expression of the character. This process would lead to
genetic assimilation. Next we show that the divergence of heritable epigenetic
marks acts to reduce or to eliminate the genetic barrier between two adaptive
peaks. Therefore, an epigenetic inheritance system can increase the probability
of transition from one adaptive state to another. Peak shift might be initiated
by (i) slight changes in the inducing environment or by (ii) genetic drift of
the genes controlling epigenetic variability. Remarkably, drift-induced
transition is facilitated even if phenotypic variation is not heritable. A
corollary of our thesis is that evolution can proceed through suboptimal
phenotypic states, without passing through a deep adaptive valley of the
genotype. We also consider the consequences of this finding on the dynamics and
mode of reproductive isolation.
Copyright 1999 Academic Press.
DOI: 10.1006/jtbi.1999.0974
PMID: 10479537 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35484099 | 1. Signal Transduct Target Ther. 2022 Apr 28;7(1):142. doi:
10.1038/s41392-022-01003-0.
Role of main RNA modifications in cancer: N(6)-methyladenosine,
5-methylcytosine, and pseudouridine.
Xue C(#)(1), Chu Q(#)(1), Zheng Q(#)(1), Jiang S(1), Bao Z(1), Su Y(1), Lu J(2),
Li L(3).
Author information:
(1)State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
National Clinical Research Center for Infectious Diseases, Collaborative
Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First
Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003,
China.
(2)State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
National Clinical Research Center for Infectious Diseases, Collaborative
Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First
Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003,
China. [email protected].
(3)State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
National Clinical Research Center for Infectious Diseases, Collaborative
Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First
Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003,
China. [email protected].
(#)Contributed equally
Cancer is one of the major diseases threatening human life and health worldwide.
Epigenetic modification refers to heritable changes in the genetic material
without any changes in the nucleic acid sequence and results in heritable
phenotypic changes. Epigenetic modifications regulate many biological processes,
such as growth, aging, and various diseases, including cancer. With the
advancement of next-generation sequencing technology, the role of RNA
modifications in cancer progression has become increasingly prominent and is a
hot spot in scientific research. This review studied several common RNA
modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine.
The deposition and roles of these modifications in coding and noncoding RNAs are
summarized in detail. Based on the RNA modification background, this review
summarized the expression, function, and underlying molecular mechanism of these
modifications and their regulators in cancer and further discussed the role of
some existing small-molecule inhibitors. More in-depth studies on RNA
modification and cancer are needed to broaden the understanding of epigenetics
and cancer diagnosis, treatment, and prognosis.
© 2022. The Author(s).
DOI: 10.1038/s41392-022-01003-0
PMCID: PMC9051163
PMID: 35484099 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/25421652 | 1. Methods Mol Biol. 2015;1238:3-25. doi: 10.1007/978-1-4939-1804-1_1.
Cancer epigenetics: an introduction.
Kanwal R(1), Gupta K, Gupta S.
Author information:
(1)Department of Urology, Case Western Reserve University, 10900 Euclid Avenue,
Cleveland, OH, 44106, USA.
Epigenetic and genetic alterations contribute to cancer initiation and
progression. Epigenetics refers to the study of heritable changes in gene
expression without alterations in DNA sequences. Epigenetic changes are
reversible and include key processes of DNA methylation, chromatin
modifications, nucleosome positioning, and alterations in noncoding RNA
profiles. Disruptions in epigenetic processes can lead to altered gene function
and cellular neoplastic transformation. Epigenetic modifications precede genetic
changes and usually occur at an early stage in neoplastic development. Recent
technological advances offer a better understanding of the underlying epigenetic
alterations during carcinogenesis and provide insight into the discovery of
putative epigenetic biomarkers for detection, prognosis, risk assessment, and
disease monitoring. In this chapter we provide information on various epigenetic
mechanisms and their role in carcinogenesis, in particular, epigenetic
modifications causing genetic changes and the potential clinical impact of
epigenetic research in the future.
DOI: 10.1007/978-1-4939-1804-1_1
PMID: 25421652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14652236 | 1. J Natl Cancer Inst. 2003 Dec 3;95(23):1747-57. doi: 10.1093/jnci/dig109.
The epigenome as a target for cancer chemoprevention.
Kopelovich L(1), Crowell JA, Fay JR.
Author information:
(1)Chemopreventive Agent Development Research Group, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892, USA. [email protected]
Epigenetic events, a key driving force in the development of cancer, are
alterations in gene expression without changes in the DNA coding sequence that
are heritable through cell division. Such changes occur throughout all stages of
tumorigenesis, including the early phases, and are increasingly recognized as
major mechanisms involved in silencing tumor suppressor genes. Epigenetic
changes can be reversed by the use of small molecules and, thus, such changes
are promising targets for cancer chemopreventive drug development. This review
examines the basis for targeting the epigenome as a prevention strategy,
focusing on understanding the epigenetic changes that occur before the
development of frank malignancy, when chemopreventive intervention will have the
maximal impact.
DOI: 10.1093/jnci/dig109
PMID: 14652236 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33809396 | 1. Cancers (Basel). 2021 Mar 12;13(6):1272. doi: 10.3390/cancers13061272.
Switching off Cancer: Is There a Role for Epigenetics?
Avery-Kiejda KA(1)(2).
Author information:
(1)School of Biomedical Sciences and Pharmacy, College of Health, Medicine and
Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia.
(2)Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
Epigenetics is the study of heritable changes in gene expression that do not
involve any change in DNA sequence and include methylation, histone
modifications, and altered miRNA or lncRNA expression [...].
DOI: 10.3390/cancers13061272
PMCID: PMC7998574
PMID: 33809396
Conflict of interest statement: The author declares no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30414795 | 1. Chest. 2019 Apr;155(4):816-824. doi: 10.1016/j.chest.2018.10.038. Epub 2018
Nov 8.
Epigenetic Changes in Airway Smooth Muscle as a Driver of Airway Inflammation
and Remodeling in Asthma.
Kaczmarek KA(1), Clifford RL(1), Knox AJ(2).
Author information:
(1)Division of Respiratory Medicine, Nottingham University Hospitals NHS Trust
(City Hospital Campus); and the Nottingham NIHR Biomedical Research Centre,
Nottingham MRC Molecular Pathology Node.
(2)Division of Respiratory Medicine, Nottingham University Hospitals NHS Trust
(City Hospital Campus); and the Nottingham NIHR Biomedical Research Centre,
Nottingham MRC Molecular Pathology Node. Electronic address:
[email protected].
Epigenetic changes are heritable changes in gene expression, without changing
the DNA sequence. Epigenetic processes provide a critical link between
environmental insults to the airway and functional changes that determine how
airway cells respond to future stimuli. There are three primary epigenetic
processes: histone modifications, DNA modification, and noncoding RNAs. Airway
smooth muscle has several important roles in the development and maintenance of
the pathologic processes occurring in asthma, including inflammation,
remodeling, and contraction/hyperresponsiveness. In this review, we describe the
evidence for the role of epigenetic changes in driving these processes in airway
smooth muscle cells in asthma, with a particular focus on histone modifications.
We also discuss how existing therapies may target some of these changes and how
epigenetic processes provide targets for the development of novel asthma
therapeutics. Epigenetic marks may also provide a biomarker to assess phenotype
and treatment responses.
Copyright © 2018 American College of Chest Physicians. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.chest.2018.10.038
PMID: 30414795 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27730435 | 1. Adv Exp Med Biol. 2016;933:59-68. doi: 10.1007/978-981-10-2041-4_6.
Epigenetic Regulation in Cystogenesis.
Woo YM(1).
Author information:
(1)Molecular Medicine Laboratory, Department of Life systems, Sookmyung Women's
University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, South Korea.
[email protected].
Epigenetic regulation refers to heritable changes in gene expression that do not
involve any alteration of the DNA sequence. DNA methylation, histone
modification, and gene regulation by microRNAs are well-known epigenetic
modulations that are closely associated with several cellular processes and
diverse disease states, such as cancers, even under precancerous conditions.
More recently, several studies have indicated that epigenetic changes may be
associated with renal cystic diseases, including autosomal dominant polycystic
kidney disease, and the restoration of altered epigenetic factors may become a
therapeutic target of renal cystic disease and would be expected to have minimal
side effects. This review focuses on recently reported findings on epigenetic
and considers the potential of targeting epigenetic regulation as a novel
therapeutic approach to control cystogenesis.
DOI: 10.1007/978-981-10-2041-4_6
PMID: 27730435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20003072 | 1. New Phytol. 2010 Mar;185(4):1108-18. doi: 10.1111/j.1469-8137.2009.03121.x.
Epub 2009 Dec 14.
Stress-induced DNA methylation changes and their heritability in asexual
dandelions.
Verhoeven KJ(1), Jansen JJ, van Dijk PJ, Biere A.
Author information:
(1)Department of Terrestrial Ecology, Netherlands Institute of Ecology
(NIOO-KNAW), Heteren, the Netherlands. [email protected]
Comment in
New Phytol. 2010 Mar;185(4):867-8. doi: 10.1111/j.1469-8137.2010.03189.x.
*DNA methylation can cause heritable phenotypic modifications in the absence of
changes in DNA sequence. Environmental stresses can trigger methylation changes
and this may have evolutionary consequences, even in the absence of sequence
variation. However, it remains largely unknown to what extent environmentally
induced methylation changes are transmitted to offspring, and whether observed
methylation variation is truly independent or a downstream consequence of
genetic variation between individuals. *Genetically identical apomictic
dandelion (Taraxacum officinale) plants were exposed to different ecological
stresses, and apomictic offspring were raised in a common unstressed
environment. We used methylation-sensitive amplified fragment length
polymorphism markers to screen genome-wide methylation alterations triggered by
stress treatments and to assess the heritability of induced changes. *Various
stresses, most notably chemical induction of herbivore and pathogen defenses,
triggered considerable methylation variation throughout the genome. Many
modifications were faithfully transmitted to offspring. Stresses caused some
epigenetic divergence between treatment and controls, but also increased
epigenetic variation among plants within treatments. *These results show the
following. First, stress-induced methylation changes are common and are mostly
heritable. Second, sequence-independent, autonomous methylation variation is
readily generated. This highlights the potential of epigenetic inheritance to
play an independent role in evolutionary processes, which is superimposed on the
system of genetic inheritance.
DOI: 10.1111/j.1469-8137.2009.03121.x
PMID: 20003072 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18550486 | 1. Yi Chuan. 2008 Jun;30(6):665-70. doi: 10.3724/sp.j.1005.2008.00665.
[The role of epigenetic regulation in etiology of major depressive disorder].
[Article in Chinese]
Dang YH(1), Li SB, Sun ZS.
Author information:
(1)Department of Forensic Sciences, College of Medicine, Xi'an Jiaotong
University, Xi'an 710061, China. [email protected]
Epigenetics refers to the heritable, but reversible, regulation of various
biological functions mediated principally through changes in DNA methylation and
chromatin structure derived from histone modification. Recent research indicated
that epigenetic mechanisms may play vital role in etiology of major psychosis,
such as schizophrenia, bipolar disorder and drug addiction. With brief
introduction of epigenetic molecular mechanisms and relevance of epigenetics to
human common diseases, this review focuses on epigenetic hypothesis and some
supporting evidence which are recently emerged in major depressive disorder
(MDD).
DOI: 10.3724/sp.j.1005.2008.00665
PMID: 18550486 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18704881 | 1. Planta Med. 2008 Oct;74(13):1593-601. doi: 10.1055/s-2008-1081347. Epub 2008
Aug 14.
Targeting epigenetic mechanisms: potential of natural products in cancer
chemoprevention.
Hauser AT(1), Jung M.
Author information:
(1)Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg,
Germany.
The term epigenetics is defined as heritable changes in gene expression patterns
that occur without changes in DNA sequence. Epigenetic changes according to this
definition are achieved by methylation of cytosine bases in the DNA and by
histone modifications, such as acetylation, methylation or phosphorylation.
These modifications play an important role in regulating gene expression and the
existence of an epigenetic code which maintains these modifications even upon
cell division has been underlined by many investigations. Targeting the enzymes
which catalyze DNA methylation or histone modifications may be a possibility not
only for cancer therapy but also for chemoprevention since disruption of
epigenetic balance is known to cause diseases such as cancer. In this review, we
want to present the key epigenetic targets. We highlight natural products that
modulate these epigenetic mechanisms and show their potential for cancer
chemoprevention.
DOI: 10.1055/s-2008-1081347
PMID: 18704881 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21941617 | 1. Genes Cancer. 2011 Jun;2(6):607-17. doi: 10.1177/1947601910393957.
DNA methylation: superior or subordinate in the epigenetic hierarchy?
Jin B(1), Li Y, Robertson KD.
Author information:
(1)Department of Biochemistry & Molecular Biology, Medical College of Georgia
Cancer Center, Augusta, GA, USA.
Epigenetic modifications are heritable changes in gene expression not encoded by
the DNA sequence. In the past decade, great strides have been made in
characterizing epigenetic changes during normal development and in disease
states like cancer. However, the epigenetic landscape has grown increasingly
complicated, encompassing DNA methylation, the histone code, noncoding RNA, and
nucleosome positioning, along with DNA sequence. As a stable repressive mark,
DNA methylation, catalyzed by the DNA methyltransferases (DNMTs), is regarded as
a key player in epigenetic silencing of transcription. DNA methylation may
coordinately regulate the chromatin status via the interaction of DNMTs with
other modifications and with components of the machinery mediating those marks.
In this review, we will comprehensively examine the current understanding of the
connections between DNA methylation and other epigenetic marks and discuss
molecular mechanisms of transcriptional repression in development and in
carcinogenesis.
DOI: 10.1177/1947601910393957
PMCID: PMC3174260
PMID: 21941617
Conflict of interest statement: The author(s) declared no potential conflicts of
interest with respect to the authorship and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/32445090 | 1. Adv Exp Med Biol. 2020;1253:3-55. doi: 10.1007/978-981-15-3449-2_1.
Epigenetics in Health and Disease.
Zhang L(1), Lu Q(1), Chang C(2)(3).
Author information:
(1)Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics,
Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
(2)Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's
Hospital, Hollywood, FL, 33021, USA. [email protected].
(3)Division of Rheumatology, Allergy and Clinical Immunology, University of
California Davis, Davis, CA, 95616, USA. [email protected].
Epigenetic mechanisms, which include DNA methylation, histone modification, and
microRNA (miRNA), can produce heritable phenotypic changes without a change in
DNA sequence. Disruption of gene expression patterns which are governed by
epigenetics can result in autoimmune diseases, cancers, and various other
maladies. Mechanisms of epigenetics include DNA methylation (and demethylation),
histone modifications, and non-coding RNAs such as microRNAs. Compared to
numerous studies that have focused on the field of genetics, research on
epigenetics is fairly recent. In contrast to genetic changes, which are
difficult to reverse, epigenetic aberrations can be pharmaceutically reversible.
The emerging tools of epigenetics can be used as preventive, diagnostic, and
therapeutic markers. With the development of drugs that target the specific
epigenetic mechanisms involved in the regulation of gene expression, development
and utilization of epigenetic tools are an appropriate and effective approach
that can be clinically applied to the treatment of various diseases.
DOI: 10.1007/978-981-15-3449-2_1
PMID: 32445090 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31301046 | 1. Adv Exp Med Biol. 2019;1166:57-74. doi: 10.1007/978-3-030-21664-1_4.
Epigenetic Transgenerational Inheritance.
Blanco Rodríguez J(1), Camprubí Sánchez C(2)(3)(4).
Author information:
(1)Genetics of Male Fertility Group, Unitat de Biologia Cel·lular (Facultat de
Biociències), Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del
Vallès), Spain. [email protected].
(2)GenIntegral, Barcelona, Spain.
(3)Reference Laboratory Genetics, L'Hospitalet de Llobregat, Spain.
(4)Unitat de Biologia Cel·lular i Genètica Mèdica (Facultat de Medicina),
Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
Epigenetic information refers to heritable changes in gene expression that occur
without modifications at the DNA sequence level. These changes are orchestrated
by different epigenetic mechanisms such as DNA methylation, posttranslational
modifications of histones, and the presence of noncoding RNAs. Epigenetic
information regulates chromatin structure to confer cell-specific gene
expression.The sperm epigenome is the result of three periods of global
resetting during men's life. Germ cell epigenome reprogramming is designed to
allow cell totipotency and to prevent the transmission of epimutations via
spermatozoa. At the end of these reprogramming events, the sperm epigenome has a
very specific epigenetic pattern that is a footprint of past reprogramming
events and has an influence on embryo development.Several data demonstrate that
not all regions of the epigenome are erased during the reprogramming periods,
suggesting the transmission of epigenetic information from fathers to offspring
via spermatozoa. Moreover, it is becoming increasingly clear that the sperm
epigenome is sensitive to environmental factors during the process of gamete
differentiation, suggesting the plasticity of the sperm epigenetic signature
according to the circumstances of the individual's life.In this chapter, we
provided strong evidences about the association between variations of the sperm
epigenome and the exposure to environmental factors. Moreover, we will present
data about how epigenetic mechanisms are candidates for transferring paternal
environmental information to offspring.
DOI: 10.1007/978-3-030-21664-1_4
PMID: 31301046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29732172 | 1. Environ Epigenet. 2018 Apr 26;4(2):dvy008. doi: 10.1093/eep/dvy008.
eCollection 2018 Apr.
Transgenerational epigenetic inheritance in birds.
Guerrero-Bosagna C(1), Morisson M(2), Liaubet L(2), Rodenburg TB(3), de Haas
EN(3), Košťál Ľ(4), Pitel F(2).
Author information:
(1)Avian Behavioural Genomics and Physiology Group, IFM Biology, Linköping
University, Linköping 58 183, Sweden.
(2)GenPhySE, Université de Toulouse, INRA, ENVT, F-31326 Castanet-Tolosan,
France.
(3)Behavioural Ecology Group, Wageningen University, 6700 AH Wageningen, The
Netherlands.
(4)Centre of Biosciences, Slovak Academy of Sciences, 840 05 Bratislava,
Slovakia.
While it has been shown that epigenetics accounts for a portion of the
variability of complex traits linked to interactions with the environment, the
real contribution of epigenetics to phenotypic variation remains to be assessed.
In recent years, a growing number of studies have revealed that epigenetic
modifications can be transmitted across generations in several animal species.
Numerous studies have demonstrated inter- or multi-generational effects of
changing environment in birds, but very few studies have been published showing
epigenetic transgenerational inheritance in these species. In this review, we
mention work conducted in parent-to-offspring transmission analyses in bird
species, with a focus on the impact of early stressors on behaviour. We then
present recent advances in transgenerational epigenetics in birds, which involve
germline linked non-Mendelian inheritance, underline the advantages and
drawbacks of working on birds in this field and comment on future directions of
transgenerational studies in bird species.
DOI: 10.1093/eep/dvy008
PMCID: PMC5920295
PMID: 29732172 |
http://www.ncbi.nlm.nih.gov/pubmed/34489118 | 1. Trends Ecol Evol. 2021 Dec;36(12):1124-1140. doi: 10.1016/j.tree.2021.08.006.
Epub 2021 Sep 3.
Epigenetic inheritance and reproductive mode in plants and animals.
Anastasiadi D(1), Venney CJ(2), Bernatchez L(2), Wellenreuther M(3).
Author information:
(1)The New Zealand Institute for Plant and Food Research Ltd, Nelson Research
Centre, 293 Akersten St, Nelson 7010, New Zealand.
(2)Institut de Biologie Intégrative des Systèmes (IBIS), Département de
Biologie, Université Laval, 1030 Avenue de la Médecine, G1V 0A6, Québec, QC,
Canada.
(3)The New Zealand Institute for Plant and Food Research Ltd, Nelson Research
Centre, 293 Akersten St, Nelson 7010, New Zealand; School of Biological
Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand.
Electronic address: [email protected].
Epigenetic inheritance is another piece of the puzzle of nongenetic inheritance,
although the prevalence, sources, persistence, and phenotypic consequences of
heritable epigenetic marks across taxa remain unclear. We systematically
reviewed over 500 studies from the past 5 years to identify trends in the
frequency of epigenetic inheritance due to differences in reproductive mode and
germline development. Genetic, intrinsic (e.g., disease), and extrinsic (e.g.,
environmental) factors were identified as sources of epigenetic inheritance,
with impacts on phenotype and adaptation depending on environmental
predictability. Our review shows that multigenerational persistence of
epigenomic patterns is common in both plants and animals, but also highlights
many knowledge gaps that remain to be filled. We provide a framework to guide
future studies towards understanding the generational persistence and
eco-evolutionary significance of epigenomic patterns.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tree.2021.08.006
PMID: 34489118 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests No interests are
declared. |
http://www.ncbi.nlm.nih.gov/pubmed/30160987 | 1. Annu Rev Genet. 2018 Nov 23;52:21-41. doi:
10.1146/annurev-genet-120417-031404. Epub 2018 Aug 30.
Transgenerational Epigenetic Inheritance.
Bošković A(1), Rando OJ(1).
Author information:
(1)Department of Biochemistry and Molecular Pharmacology, University of
Massachusetts Medical School, Worcester, Massachusetts 01605, USA; email:
[email protected].
Inheritance of genomic DNA underlies the vast majority of biological
inheritance, yet it has been clear for decades that additional epigenetic
information can be passed on to future generations. Here, we review major model
systems for transgenerational epigenetic inheritance via the germline in
multicellular organisms. In addition to surveying examples of epivariation that
may arise stochastically or in response to unknown stimuli, we also discuss the
induction of heritable epigenetic changes by genetic or environmental
perturbations. Mechanistically, we discuss the increasingly well-understood
molecular pathways responsible for epigenetic inheritance, with a focus on the
unusual features of the germline epigenome.
DOI: 10.1146/annurev-genet-120417-031404
PMID: 30160987 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34070712 | 1. Plants (Basel). 2021 May 30;10(6):1096. doi: 10.3390/plants10061096.
In Response to Abiotic Stress, DNA Methylation Confers EpiGenetic Changes in
Plants.
Akhter Z(1), Bi Z(1), Ali K(1)(2), Sun C(1), Fiaz S(3), Haider FU(4), Bai J(1).
Author information:
(1)Gansu Provincial Key Laboratory of Aridland Crop Science; Department of Crop
Genetics & Breeding, College of Agronomy, Gansu Agricultural University, Lanzhou
730070, China.
(2)National Institute for Genomics and Advanced Biotechnology, National
Agricultural Research Centre, Park Road, Islamabad 45500, Pakistan.
(3)Department of Plant Breeding and Genetics, The University of Haripur, Haripur
22600, Pakistan.
(4)College of Resources and Environmental Sciences, Gansu Agricultural
University, Lanzhou 730070, China.
Epigenetics involves the heritable changes in patterns of gene expression
determined by developmental and abiotic stresses, i.e., drought, cold, salinity,
trace metals, and heat. Gene expression is driven by changes in DNA bases,
histone proteins, the biogenesis of ncRNA, and changes in the nucleotide
sequence. To cope with abiotic stresses, plants adopt certain changes driven by
a sophisticated biological system. DNA methylation is a primary mechanism for
epigenetic variation, which can induce phenotypic alterations in plants under
stress. Some of the stress-driven changes in plants are temporary, while some
modifications may be stable and inheritable to the next generations to allow
them to cope with such extreme stress challenges in the future. In this review,
we discuss the pivotal role of epigenetically developed phenotypic
characteristics in plants as an evolutionary process participating in adaptation
and tolerance responses to abiotic and biotic stresses that alter their growth
and development. We emphasize the molecular process underlying changes in DNA
methylation, differential variation for different species, the roles of
non-coding RNAs in epigenetic modification, techniques for studying DNA
methylation, and its role in crop improvement in tolerance to abiotic stress
(drought, salinity, and heat). We summarize DNA methylation as a significant
future research priority for tailoring crops according to various challenging
environmental issues.
DOI: 10.3390/plants10061096
PMCID: PMC8227271
PMID: 34070712
Conflict of interest statement: The authors declare that they have no competing
interest. |