Special Issue "DNA Methylation"

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

Deadline for manuscript submissions: closed (30 April 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Melanie Ehrlich

Hayward Human Genetics Center, Tulane Cancer Center, and the Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, USA
Website | E-Mail
Interests: DNA methylation; chromatin epigenetics; regulation of skeletal muscle development; cancer epigenetics

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

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 600 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

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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Open AccessArticle Myogenic Differential Methylation: Diverse Associations with Chromatin Structure
Biology 2014, 3(2), 426-451; doi:10.3390/biology3020426
Received: 18 April 2014 / Revised: 21 May 2014 / Accepted: 21 May 2014 / Published: 19 June 2014
PDF Full-text (370 KB) | HTML Full-text | XML Full-text | Supplementary Files
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

Jump to: Research

Open AccessReview DNA Methylation Analysis: Choosing the Right Method
Biology 2016, 5(1), 3; doi:10.3390/biology5010003
Received: 8 July 2015 / Revised: 16 December 2015 / Accepted: 22 December 2015 / Published: 6 January 2016
Cited by 5 | PDF Full-text (1848 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Mammalian Non-CpG Methylation: Stem Cells and Beyond
Biology 2014, 3(4), 739-751; doi:10.3390/biology3040739
Received: 9 June 2014 / Revised: 4 November 2014 / Accepted: 5 November 2014 / Published: 11 November 2014
Cited by 8 | PDF Full-text (89 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview DNA Modifications: Function and Applications in Normal and Disease States
Biology 2014, 3(4), 670-723; doi:10.3390/biology3040670
Received: 15 July 2014 / Revised: 22 September 2014 / Accepted: 24 September 2014 / Published: 22 October 2014
Cited by 14 | PDF Full-text (1803 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Regulated DNA Methylation and the Circadian Clock: Implications in Cancer
Biology 2014, 3(3), 560-577; doi:10.3390/biology3030560
Received: 7 May 2014 / Revised: 12 August 2014 / Accepted: 15 August 2014 / Published: 5 September 2014
Cited by 6 | PDF Full-text (1037 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases
Biology 2014, 3(3), 578-605; doi:10.3390/biology3030578
Received: 18 May 2014 / Revised: 18 July 2014 / Accepted: 21 August 2014 / Published: 5 September 2014
Cited by 6 | PDF Full-text (1000 KB) | HTML Full-text | XML Full-text
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)
Figures

Open AccessReview Preterm Birth and Its Long-Term Effects: Methylation to Mechanisms
Biology 2014, 3(3), 498-513; doi:10.3390/biology3030498
Received: 26 May 2014 / Revised: 8 August 2014 / Accepted: 12 August 2014 / Published: 21 August 2014
Cited by 7 | PDF Full-text (149 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Control of Glycosylation-Related Genes by DNA Methylation: the Intriguing Case of the B3GALT5 Gene and Its Distinct Promoters
Biology 2014, 3(3), 484-497; doi:10.3390/biology3030484
Received: 28 April 2014 / Revised: 22 July 2014 / Accepted: 25 July 2014 / Published: 4 August 2014
Cited by 2 | PDF Full-text (799 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Causes and Consequences of Age-Related Changes in DNA Methylation: A Role for ROS?
Biology 2014, 3(2), 403-425; doi:10.3390/biology3020403
Received: 14 May 2014 / Revised: 28 May 2014 / Accepted: 31 May 2014 / Published: 18 June 2014
Cited by 9 | PDF Full-text (253 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview RNA Splicing Factors and RNA-Directed DNA Methylation
Biology 2014, 3(2), 243-254; doi:10.3390/biology3020243
Received: 17 February 2014 / Revised: 18 March 2014 / Accepted: 20 March 2014 / Published: 26 March 2014
Cited by 3 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
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)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Dnmt3b prefers germline genes and centromeric regions: implications for diseases
Authors: Emma Walton, Guillaume Velasco and Claire Francastel
Affiliations: UMR7216 Epigenetics and Cell Fate, CNRS, Université Paris 7, Paris, France; E-Mail: claire.francastel@univ-paris-diderot.fr
Abstract: Correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, chromatin structure modulation, 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, changes to patterns of DNA methylation are commonly observed in diseases with chromosomal and genomic instabilities. In this context, expression or catalytic activity of the enzymes that catalyze the modification, the DNA methyltransferases (DNMT), appear to be particularly affected. DNMT3B, involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its strong links to disease. Catalytically inactive variants have been associated with cancer risk and germline hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, a global genomic hypomethylation affects repeated sequences around centromeric regions, the main hallmark of heterochromatin, in association with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data on the activity of Dnmt3b and its variants, and the consequences of its deregulated activity on pathological DNA hypomethylation, illicit activation of germline-specific genes and accumulation of transcripts originating from repeated satellite sequences as original physiopathological biomarkers for these diseases. We will also question the potential functional impact of these deregulated protein-coding and non-coding transcription programs on perturbation of cellular and nuclear phenotypes.

Type of Paper: Review
Title: DNA methylation analysis: Methods
Author: Sergey Kurdyukov
Affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia; E-Mail: sergey.kurdyukov@sydney.edu.au
Abstract: In the burgeoning field of epigenetics there are a number of methods for DNA methylation analysis. How one could find the right method to answers a specific biological question? The review is aiming to provide an algorithm for researchers that are new to the area. All modern techniques for DNA methylation analysis are scrutinized and ranked according to their robustness, high throughput capabilities and cost. Separate sections are dedicated to methods that are suitable for investigation of global methylation profiling and methylation status of specific genes of interest.

Type of Paper: Review
Title: DNA methylation, genome evolution and phenotypic divergence
Authors: Kei Fukuda and Kenji Ichiyanagi *
Affiliation: Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; E-Mail:
ichiyanagi@bioreg.kyushu-u.ac.jp
Abstract: Epigenetic regulation by DNA methylation plays important roles in gene regulation, transposon silencing, cell differentiation, ontogenesis, and pathogenesis in the mammalian system. The epigenome can be altered in response to environmental changes, leading to phenotypic changes, and the altered state of epigenome is in some cases inherited across generations. Recent comparative studies on DNA methylation between different species and within population of a species have revealed the importance of DNA methylation in phenotypic divergence and evolution. However, the molecular mechanisms that alter the DNA methylation pattern remains largely unknown. In this review, we summarize the current understanding on genome-epigenome interactions and discuss their implications in mammalian evolution and human diseases.

Type of Paper: Review
Title: DNA modifications: function and applications in normal and disease states
Authors: Vichithra R B Liyanage 1, Jessica Jarmasz 2, Marc R Del Bigio 3, Mojgan Rastegar 1 and James R Davie 1,*
Affiliations:
1
Department of Biochemistry and Medical Genetics, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada; E-Mail: davie@cc.umanitoba.ca
2
Department of Human Anatomy and Cell Science, University of Manitoba
3
Department of Pathology, University of Manitoba
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 genome function. Methylation of DNA at the 5th position of cytosine in CpG dinucleotides (5-methylcytosine, 5-mC), which is carried out by DNA methyltransferases, is commonly associated with gene silencing. However, high resolution mapping of DNA methylation has revealed that 5-mC 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 (5-hmC), which is a product of the TET proteins converting 5-mC to 5-hmC. In this review, we will highlight current studies on the role of 5-mC and 5-hmC in regulating gene expression. Further the role of these modifications in and detection of pathological states (type 2 diabetes, Rett syndrome, and Fetal alcohol spectrum disorders) will be discussed.

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