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DNA Methylation
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DNA Methylation

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (30 April 2014) | Viewed by 125746

Special Issue Editor

Prof. Dr. Melanie Ehrlich

E-Mail Website
Guest Editor
Hayward Human Genetics Center, Tulane Cancer Center, and the Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Interests: DNA methylation; chromatin epigenetics; regulation of skeletal muscle development; cancer epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Improvements in methodology for analyzing animal and plant DNA methylation, especially in genome-wide studies (methylome analysis), are bringing new insights into the functions of modification of genomic cytosine residues(5-methylcytosine, 5mC, and the much less plentiful 5-hydroxymethylcytosine, 5hmC). DNA methylation profiles coupled with data on gene expression, histone modification, transcription factor binding, open chromatin and the results of experimental manipulation of DNA methylation are greatly advancing our understanding of the roles of genomic 5mC in normal development, physiology, and disease. These studies are revealing increasingly varied and context-dependent consequences of increases and decreases in DNA methylation on gene expression that are only beginning to be generally recognized.

Recent investigations of mammalian genomic 5hmC, which is generated from 5mC residues, indicate distinct functional and chromatin structural associations from those of 5mC. The role of genomic 5hmC as an intermediate in the conversion of 5mC to unmodified C residues and the biological significance of the stable fraction of this DNA base in differentiation, cellular function (especially in the nervous system), and pathology are being intensively investigated. Tissue-specific differences and cancer-associated reductions in genomic 5hmC content suggest not only its importance in vivo, but also reaffirm that of the parent 5mC DNA residue. For this special issue we invite research articles on any of the frontiers of DNA methylation research.

Prof. Dr. Melanie Ehrlich
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA methylation
  • methylome epigenetics
  • chromatin modification
  • 5-methylcytosine
  • 5-hydroxymethylcytosine
  • development
  • cancer
  • regulation of gene expression

Published Papers (10 papers)

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Research

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370 KiB  
Article
Myogenic Differential Methylation: Diverse Associations with Chromatin Structure
by Sruti Chandra, Carl Baribault, Michelle Lacey and Melanie Ehrlich
Biology 2014, 3(2), 426-451; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3020426 - 19 Jun 2014
Cited by 12 | Viewed by 8756
Abstract
Employing a new algorithm for identifying differentially methylated regions (DMRs) from reduced representation bisulfite sequencing profiles, we identified 1972 hypermethylated and 3250 hypomethylated myogenic DMRs in a comparison of myoblasts (Mb) and myotubes (Mt) with 16 types of nonmuscle cell cultures. DMRs co-localized [...] Read more.
Employing a new algorithm for identifying differentially methylated regions (DMRs) from reduced representation bisulfite sequencing profiles, we identified 1972 hypermethylated and 3250 hypomethylated myogenic DMRs in a comparison of myoblasts (Mb) and myotubes (Mt) with 16 types of nonmuscle cell cultures. DMRs co-localized with a variety of chromatin structures, as deduced from ENCODE whole-genome profiles. Myogenic hypomethylation was highly associated with both weak and strong enhancer-type chromatin, while hypermethylation was infrequently associated with enhancer-type chromatin. Both myogenic hypermethylation and hypomethylation often overlapped weak transcription-type chromatin and Polycomb-repressed-type chromatin. For representative genes, we illustrate relationships between DNA methylation, the local chromatin state, DNaseI hypersensitivity, and gene expression. For example, MARVELD2 exhibited myogenic hypermethylation in transcription-type chromatin that overlapped a silenced promoter in Mb and Mt while TEAD4 had myogenic hypomethylation in intronic subregions displaying enhancer-type or transcription-type chromatin in these cells. For LSP1, alternative promoter usage and active promoter-type chromatin were linked to highly specific myogenic or lymphogenic hypomethylated DMRs. Lastly, despite its myogenesis-associated expression, TBX15 had multiple hypermethylated myogenic DMRs framing its promoter region. This could help explain why TBX15 was previously reported to be underexpressed and, unexpectedly, its promoter undermethylated in placentas exhibiting vascular intrauterine growth restriction. Full article
(This article belongs to the Special Issue DNA Methylation)
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Review

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1848 KiB  
Review
DNA Methylation Analysis: Choosing the Right Method
by Sergey Kurdyukov and Martyn Bullock
Biology 2016, 5(1), 3; https://0-doi-org.brum.beds.ac.uk/10.3390/biology5010003 - 06 Jan 2016
Cited by 467 | Viewed by 34004
Abstract
In the burgeoning field of epigenetics, there are several methods available to determine the methylation status of DNA samples. However, choosing the method that is best suited to answering a particular biological question still proves to be a difficult task. This review aims [...] Read more.
In the burgeoning field of epigenetics, there are several methods available to determine the methylation status of DNA samples. However, choosing the method that is best suited to answering a particular biological question still proves to be a difficult task. This review aims to provide biologists, particularly those new to the field of epigenetics, with a simple algorithm to help guide them in the selection of the most appropriate assay to meet their research needs. First of all, we have separated all methods into two categories: those that are used for: (1) the discovery of unknown epigenetic changes; and (2) the assessment of DNA methylation within particular regulatory regions/genes of interest. The techniques are then scrutinized and ranked according to their robustness, high throughput capabilities and cost. This review includes the majority of methods available to date, but with a particular focus on commercially available kits or other simple and straightforward solutions that have proven to be useful. Full article
(This article belongs to the Special Issue DNA Methylation)
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89 KiB  
Review
Mammalian Non-CpG Methylation: Stem Cells and Beyond
by Sara E. Pinney
Biology 2014, 3(4), 739-751; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3040739 - 11 Nov 2014
Cited by 69 | Viewed by 8741
Abstract
Although CpG dinucleotides remain the primary site for DNA methylation in mammals, there is emerging evidence that DNA methylation at non-CpG sites (CpA, CpT and CpC) is not only present in mammalian cells, but may play a unique role in the regulation of [...] Read more.
Although CpG dinucleotides remain the primary site for DNA methylation in mammals, there is emerging evidence that DNA methylation at non-CpG sites (CpA, CpT and CpC) is not only present in mammalian cells, but may play a unique role in the regulation of gene expression. For some time it has been known that non-CpG methylation is abundant in plants and present in mammalian embryonic stem cells, but non-CpG methylation was thought to be lost upon cell differentiation. However, recent publications have described a role for non-CpG methylation in adult mammalian somatic cells including the adult mammalian brain, skeletal muscle, and hematopoietic cells and new interest in this field has been stimulated by the availability of high throughput sequencing techniques that can accurately measure this epigenetic modification. Genome wide assays indicate that non-CpG methylation is negligible in human fetal brain, but abundant in human adult brain tissue. Genome wide measurement of non-CpG methylation coupled with RNA-Sequencing indicates that in the human adult brain non-CpG methylation levels are inversely proportional to the abundance of mRNA transcript at the associated gene. Additionally specific examples where alterations in non-CpG methylation lead to changes in gene expression have been described; in PGC1α in human skeletal muscle, IFN-γ in human T-cells and SYT11 in human brain, all of which contribute to the development of human disease. Full article
(This article belongs to the Special Issue DNA Methylation)
1803 KiB  
Review
DNA Modifications: Function and Applications in Normal and Disease States
by Vichithra R. B. Liyanage, Jessica S. Jarmasz, Nanditha Murugeshan, Marc R. Del Bigio, Mojgan Rastegar and James R. Davie
Biology 2014, 3(4), 670-723; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3040670 - 22 Oct 2014
Cited by 113 | Viewed by 16736
Abstract
Epigenetics refers to a variety of processes that have heritable effects on gene expression programs without changes in DNA sequence. Key players in epigenetic control are chemical modifications to DNA, histone, and non-histone chromosomal proteins, which establish a complex regulatory network that controls [...] Read more.
Epigenetics refers to a variety of processes that have heritable effects on gene expression programs without changes in DNA sequence. Key players in epigenetic control are chemical modifications to DNA, histone, and non-histone chromosomal proteins, which establish a complex regulatory network that controls genome function. Methylation of DNA at the fifth position of cytosine in CpG dinucleotides (5-methylcytosine, 5mC), which is carried out by DNA methyltransferases, is commonly associated with gene silencing. However, high resolution mapping of DNA methylation has revealed that 5mC is enriched in exonic nucleosomes and at intron-exon junctions, suggesting a role of DNA methylation in the relationship between elongation and RNA splicing. Recent studies have increased our knowledge of another modification of DNA, 5-hydroxymethylcytosine (5hmC), which is a product of the ten-eleven translocation (TET) proteins converting 5mC to 5hmC. In this review, we will highlight current studies on the role of 5mC and 5hmC in regulating gene expression (using some aspects of brain development as examples). Further the roles of these modifications in detection of pathological states (type 2 diabetes, Rett syndrome, fetal alcohol spectrum disorders and teratogen exposure) will be discussed. Full article
(This article belongs to the Special Issue DNA Methylation)
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1000 KiB  
Review
Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases
by Emma L. Walton, Claire Francastel and Guillaume Velasco
Biology 2014, 3(3), 578-605; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3030578 - 05 Sep 2014
Cited by 28 | Viewed by 10140
Abstract
The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic [...] Read more.
The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes. Full article
(This article belongs to the Special Issue DNA Methylation)
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1037 KiB  
Review
Regulated DNA Methylation and the Circadian Clock: Implications in Cancer
by Tammy M. Joska, Riasat Zaman and William J. Belden
Biology 2014, 3(3), 560-577; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3030560 - 05 Sep 2014
Cited by 33 | Viewed by 10225
Abstract
Since the cloning and discovery of DNA methyltransferases (DNMT), there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has [...] Read more.
Since the cloning and discovery of DNA methyltransferases (DNMT), there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has become evident that dynamic DNA methylation accompanies the circadian clock and is found at clock genes in Neurospora, mice and cancer cells. The relationship among the circadian clock, cancer and DNA methylation at clock genes suggests a correlative indication that improper DNA methylation may influence clock gene expression, contributing to the etiology of cancer. The molecular mechanism underlying DNA methylation at clock loci is best studied in the filamentous fungi, Neurospora crassa, and recent data indicate a mechanism analogous to the RNA-dependent DNA methylation (RdDM) or RNAi-mediated facultative heterochromatin. Although it is still unclear, DNA methylation at clock genes may function as a terminal modification that serves to prevent the regulated removal of histone modifications. In this capacity, aberrant DNA methylation may serve as a readout of misregulated clock genes and not as the causative agent. This review explores the implications of DNA methylation at clock loci and describes what is currently known regarding the molecular mechanism underlying DNA methylation at circadian clock genes. Full article
(This article belongs to the Special Issue DNA Methylation)
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149 KiB  
Review
Preterm Birth and Its Long-Term Effects: Methylation to Mechanisms
by Sasha E. Parets, Carrie E. Bedient, Ramkumar Menon and Alicia K. Smith
Biology 2014, 3(3), 498-513; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3030498 - 21 Aug 2014
Cited by 39 | Viewed by 9432
Abstract
The epigenetic patterns established during development may influence gene expression over a lifetime and increase susceptibility to chronic disease. Being born preterm (<37 weeks of gestation) is associated with increased risk mortality and morbidity from birth until adulthood. This brief review explores the [...] Read more.
The epigenetic patterns established during development may influence gene expression over a lifetime and increase susceptibility to chronic disease. Being born preterm (<37 weeks of gestation) is associated with increased risk mortality and morbidity from birth until adulthood. This brief review explores the potential role of DNA methylation in preterm birth (PTB) and its possible long-term consequences and provides an overview of the physiological processes central to PTB and recent DNA methylation studies of PTB. Full article
(This article belongs to the Special Issue DNA Methylation)
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799 KiB  
Review
Control of Glycosylation-Related Genes by DNA Methylation: the Intriguing Case of the B3GALT5 Gene and Its Distinct Promoters
by Marco Trinchera, Aida Zulueta, Anna Caretti and Fabio Dall'Olio
Biology 2014, 3(3), 484-497; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3030484 - 04 Aug 2014
Cited by 14 | Viewed by 8250
Abstract
Glycosylation is a metabolic pathway consisting of the enzymatic modification of proteins and lipids through the stepwise addition of sugars that gives rise to glycoconjugates. To determine the full complement of glycoconjugates that cells produce (the glycome), a variety of genes are involved, [...] Read more.
Glycosylation is a metabolic pathway consisting of the enzymatic modification of proteins and lipids through the stepwise addition of sugars that gives rise to glycoconjugates. To determine the full complement of glycoconjugates that cells produce (the glycome), a variety of genes are involved, many of which are regulated by DNA methylation. The aim of the present review is to briefly describe some relevant examples of glycosylation-related genes whose DNA methylation has been implicated in their regulation and to focus on the intriguing case of a glycosyltransferase gene (B3GALT5). Aberrant promoter methylation is frequently at the basis of their modulation in cancer, but in the case of B3GALT5, at least two promoters are involved in regulation, and a complex interplay is reported to occur between transcription factors, chromatin remodelling and DNA methylation of typical CpG islands or even of other CpG dinucleotides. Transcription of the B3GALT5 gene underwent a particular evolutionary fate, so that promoter hypermethylation, acting on one transcript, and hypomethylation of other sequences, acting on the other, cooperate on one gene to obtain full cancer-associated silencing. The findings may also help in unravelling the complex origin of serum CA19.9 antigen circulating in some patients. Full article
(This article belongs to the Special Issue DNA Methylation)
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253 KiB  
Review
Causes and Consequences of Age-Related Changes in DNA Methylation: A Role for ROS?
by Franka J. Rang and Johannes Boonstra
Biology 2014, 3(2), 403-425; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3020403 - 18 Jun 2014
Cited by 45 | Viewed by 7886
Abstract
Recent genome-wide analysis of C-phosphate-G (CpG) sites has shown that the DNA methylome changes with increasing age, giving rise to genome-wide hypomethylation with site‑specific incidences of hypermethylation. This notion has received a lot of attention, as it potentially explains why aged organisms generally [...] Read more.
Recent genome-wide analysis of C-phosphate-G (CpG) sites has shown that the DNA methylome changes with increasing age, giving rise to genome-wide hypomethylation with site‑specific incidences of hypermethylation. This notion has received a lot of attention, as it potentially explains why aged organisms generally have a higher risk of age-related diseases. However, very little is known about the mechanisms that could cause the occurrence of these changes. Moreover, there does not appear to be a clear link between popular theories of aging and alterations in the methylome. Some of the most fruitful of these theories attribute an important role to reactive oxygen species, which seem to be responsible for an increase in oxidative damage to macromolecules, such as DNA, during the lifetime of an organism. In this review, the connection between changes in DNA methylation and these reactive oxygen species is discussed, as well as the effect of these changes on health. Deeper insights into the nature, causes and consequences of the aging methylome might provide a deeper understanding of the molecular mechanisms of aging and eventually contribute to the development of new diagnostic and therapeutic tools. Full article
(This article belongs to the Special Issue DNA Methylation)
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219 KiB  
Review
RNA Splicing Factors and RNA-Directed DNA Methylation
by Chao-Feng Huang and Jian-Kang Zhu
Biology 2014, 3(2), 243-254; https://0-doi-org.brum.beds.ac.uk/10.3390/biology3020243 - 26 Mar 2014
Cited by 13 | Viewed by 10431
Abstract
RNA-directed histone and/or DNA modification is a conserved mechanism for the establishment of epigenetic marks from yeasts and plants to mammals. The heterochromation formation in yeast is mediated by RNAi-directed silencing mechanism, while the establishment of DNA methylation in plants is through the [...] Read more.
RNA-directed histone and/or DNA modification is a conserved mechanism for the establishment of epigenetic marks from yeasts and plants to mammals. The heterochromation formation in yeast is mediated by RNAi-directed silencing mechanism, while the establishment of DNA methylation in plants is through the RNA-directed DNA methylation (RdDM) pathway. Recently, splicing factors are reported to be involved in both RNAi-directed heterochromatin formation in yeast and the RdDM pathway in plants. In yeast, splicing factors may provide a platform for facilitating the siRNA generation through an interaction with RDRC and thereby affect the heterochromatin formation, whereas in plants, various splicing factors seem to act at different steps in the RdDM pathway. Full article
(This article belongs to the Special Issue DNA Methylation)
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