scholarly journals DNA demethylation is a driver for chick retina regeneration

2019 ◽  
Author(s):  
Agustín Luz-Madrigal ◽  
Erika Grajales-Esquivel ◽  
Jared Tangeman ◽  
Sarah Kosse ◽  
Lin Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Comprehensive Analysis ◽  
Dna Demethylation ◽  
Cellular Reprogramming ◽  
Embryonic Chick ◽  
Dynamic Changes ◽  
Histone Marks ◽  
Retina Regeneration ◽  
Active Dna Demethylation ◽  
Genome Wide

ABSTRACTBackgroundA promising avenue toward human retina regeneration lies in identifying the factors that promote cellular reprogramming to retinal neurons in organisms able to undergo retina regeneration. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programs and cell identity. Here, we systematically analyzed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. We examined the dynamic changes in the levels and distribution of histone marks and DNA modifications, as well as conducted a comprehensive analysis of the DNA methylome during this process.ResultsIn addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks and intermediates of the process of DNA demethylation. At early times after injury, H3K27me3 and 5mC repression marks decreased while 5caC and the H3K4me3 activation mark increased, suggesting genome-wide changes in the bivalent chromatin, impaired DNA methylation, and active DNA demethylation in the chromatin reconfiguration of reprogramming RPE. Comprehensive analysis of the methylome by whole-genome bisulfite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. In contrast, genes associated with early RPE reprogramming are hypomethylated in the intact RPE and remain hypomethylated during the process. During the generation of a neuroepithelium (NE) at later stages of reprogramming, decreased levels of H3K27me3, 5mC, and 5hmC coincide with elevated levels of H3K27Ac and 5caC, indicating an active demethylation process and genome-wide changes in the active regulatory landscape. Finally, we identify Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration in the embryonic chick, capable of reprogramming RPE in the absence of exogenous FGF2.ConclusionOur results demonstrated that injury signals early in RPE reprogramming trigger genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2 these dynamic modifications are further sustained in the commitment to form a new retina. We identify DNA demethylation as a key process driving the process of RPE reprogramming and identified TET3 as a factor able to reprogram RPE in absence of FGF2. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals.

scholarly journals DNA demethylation is initiated in the central cells of Arabidopsis and rice

2016 ◽  
Vol 113 (52) ◽  
pp. 15138-15143 ◽  
Author(s):  
Kyunghyuk Park ◽  
M. Yvonne Kim ◽  
Martin Vickers ◽  
Jin-Sup Park ◽  
Youbong Hyun ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Dna Demethylation ◽  
Central Cell ◽  
Dna Modification ◽  
Active Dna Demethylation ◽  
Genome Wide ◽  
Regulatory Functions ◽  
Global Reduction

Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis. DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice—species that diverged 150 million years ago—as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis. However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm.

scholarly journals Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos

2020 ◽  
Vol 48 (15) ◽  
pp. 8431-8444 ◽  
Author(s):  
Byungkuk Min ◽  
Jung Sun Park ◽  
Young Sun Jeong ◽  
Kyuheum Jeon ◽  
Yong-Kook Kang
Keyword(s):  
Dna Methylation ◽  
Cpg Islands ◽  
Endogenous Retrovirus ◽  
Dna Demethylation ◽  
Mouse Development ◽  
Genome Wide ◽  
Early Embryos ◽  
Dna Adenine Methylase ◽  
Early Mouse ◽  
Early Developmental

Abstract Genome-wide passive DNA demethylation in cleavage-stage mouse embryos is related to the cytoplasmic localization of the maintenance methyltransferase DNMT1. However, recent studies provided evidences of the nuclear localization of DNMT1 and its contribution to the maintenance of methylation levels of imprinted regions and other genomic loci in early embryos. Using the DNA adenine methylase identification method, we identified Dnmt1-binding regions in four- and eight-cell embryos. The unbiased distribution of Dnmt1 peaks in the genic regions (promoters and CpG islands) as well as the absence of a correlation between the Dnmt1 peaks and the expression levels of the peak-associated genes refutes the active participation of Dnmt1 in the transcriptional regulation of genes in the early developmental period. Instead, Dnmt1 was found to associate with genomic retroelements in a greatly biased fashion, particularly with the LINE1 (long interspersed nuclear elements) and ERVK (endogenous retrovirus type K) sequences. Transcriptomic analysis revealed that the transcripts of the Dnmt1-enriched retroelements were overrepresented in Dnmt1 knockdown embryos. Finally, methyl-CpG-binding domain sequencing proved that the Dnmt1-enriched retroelements, which were densely methylated in wild-type embryos, became demethylated in the Dnmt1-depleted embryos. Our results indicate that Dnmt1 is involved in the repression of retroelements through DNA methylation in early mouse development.

scholarly journals DNA demethylation by ROS1a in rice vegetative cells promotes methylation in sperm

2019 ◽  
Vol 116 (19) ◽  
pp. 9652-9657 ◽  
Author(s):  
M. Yvonne Kim ◽  
Akemi Ono ◽  
Stefan Scholten ◽  
Tetsu Kinoshita ◽  
Daniel Zilberman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vegetative Cell ◽  
Seed Viability ◽  
Dna Demethylation ◽  
Central Cell ◽  
Dna Glycosylase ◽  
Rice Seed ◽  
Vegetative Cells ◽  
Active Dna Demethylation ◽  
Cell Genome

Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion.

scholarly journals Dynamic Changes of Genome-Wide DNA Methylation during Soybean Seed Development

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yong-qiang Charles An ◽  
Wolfgang Goettel ◽  
Qiang Han ◽  
Arthur Bartels ◽  
Zongrang Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Seed Development ◽  
Soybean Seed ◽  
Dynamic Changes ◽  
Genome Wide

scholarly journals Histone acetylation recruits the SWR1 complex to regulate active DNA demethylation in Arabidopsis

2019 ◽  
Vol 116 (33) ◽  
pp. 16641-16650 ◽  
Author(s):  
Wen-Feng Nie ◽  
Mingguang Lei ◽  
Mingxuan Zhang ◽  
Kai Tang ◽  
Huan Huang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Conceptual Framework ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Nuclear Protein ◽  
Dna Demethylation ◽  
Specific Target ◽  
Active Dna Demethylation ◽  
Chromatin Remodeling Complex ◽  
Genomic Regions

Active DNA demethylation is critical for controlling the DNA methylomes in plants and mammals. However, little is known about how DNA demethylases are recruited to target loci, and the involvement of chromatin marks in this process. Here, we identify 2 components of the SWR1 chromatin-remodeling complex, PIE1 and ARP6, as required for ROS1-mediated DNA demethylation, and discover 2 SWR1-associated bromodomain-containing proteins, AtMBD9 and nuclear protein X1 (NPX1). AtMBD9 and NPX1 recognize histone acetylation marks established by increased DNA methylation 1 (IDM1), a known regulator of DNA demethylation, redundantly facilitating H2A.Z deposition at IDM1 target loci. We show that at some genomic regions, H2A.Z and DNA methylation marks coexist, and H2A.Z physically interacts with ROS1 to regulate DNA demethylation and antisilencing. Our results unveil a mechanism through which DNA demethylases can be recruited to specific target loci exhibiting particular histone marks, providing a conceptual framework to understand how chromatin marks regulate DNA demethylation.

scholarly journals PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands

2021 ◽  
Vol 5 (1) ◽  
pp. e202101228
Author(s):  
Xiaokang Wang ◽  
Wojciech Rosikiewicz ◽  
Yurii Sedkov ◽  
Tanner Martinez ◽  
Baranda S Hansen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Cpg Islands ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Genome Wide ◽  
Associated Proteins ◽  
Tet Enzymes ◽  
Tet Protein ◽  
First Time

DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.

scholarly journals DNMT3A Mutations Enhance CpG Mutagenesis through Deregulation of the Active DNA Demethylation Pathway

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1076-1076
Author(s):  
Mathijs A. Sanders ◽  
Annelieke Zeilemaker ◽  
Adil al Hinai ◽  
Remco Hoogenboezem ◽  
François G. Kavelaars ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mismatch Repair ◽  
Somatic Mutations ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Dominant Negative Effect ◽  
Active Dna Demethylation ◽  
Mutational Pattern ◽  
Demethylation Pathway ◽  
Mutational Process

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is a clonal disorder characterized by preleukemic mutations and increases in prevalence during aging. Infrequently CHIP progresses to hematological cancer implying that preleukemic mutations subtly affect leukemogenesis but a mechanistic explanation is lacking. Exceedingly, preleukemic mutations are acquired in genes encoding for DNA methylation modifiers, predominantly in DNMT3A and members of the active DNA demethylation pathway. DNMT3A encodes a de novo methyltransferase establishing 5-methylcytosine (5mC) and mutations in this gene are linked to impaired DNA methylation and DNA damage sensing. Active DNA demethylation is carried out by two independent pathways (Figure 1A). The oxidation active repair (AOAR) pathway converts 5mC to DNA demethylation derivates which are cleaved by the DNA glycosylase TDG. The deamination pathway deaminates 5mC introducing a T/G mismatch which is cleaved by the DNA glycosylases MBD4 and TDG. Importantly, ineffective T/G mismatch repair results in C>T mutations at CpGs. Strikingly, recent studies revealed that the genomes of acute myeloid leukemia (AML) patients have a preponderance for C>T mutations at CpGs, potentially linking this mutational process to the deamination pathway. Here we present data revealing a specific mechanism by which DNMT3A gene mutations may enhance leukemogenesis through the deregulation of the active DNA demethylation pathway. A detailed understanding on the effects of DNA methylation modifier mutations was obtained from a single AML patient for whom we carried out whole exome sequencing on diagnostic and relapse specimens. At diagnosis the patient presented with 331 somatic mutations from which 324 where C>T mutations (97.8%) and at relapse his leukemia had acquired 386 somatic mutations from which 384 where C>T mutations (99.5%), which almost all (>95%) were in CpGs. We superimposed the somatic mutations on the DNA demethylation pathways to understand the pervasiveness of this mutational process in this AML patient. We detected a R132C IDH1 mutation at diagnosis and relapse effectively impairing the AOAR pathway. Thus, only ineffective T/G mismatch repair by the deamination pathway could confer this mutational pattern. Strikingly, we observed a homozygous MBD4 mutation rendering the protein catalytically inactive. However, we could not detect genetic lesions perturbing TDG. Recent studies demonstrated that DNMT3A potentiates TDG activity through interaction. Consistent with this finding the patient presented at diagnosis the hotspot R882C DNMT3A mutation while at relapse his leukemia presented with the R635W, R668C, R882C and A884V DNMT3A mutations. We investigated whether mutant DNMT3A systematically attenuates TDG activity through glycosylase activity assays with recombinant proteins. We demonstrated that incrementing wildtype DNMT3A concentration increase the TDG activity towards T/G-mismatches. In contrast, we found that recombinant DNMT3A with mutations at R668C, R882C and A884V rapidly decrease TDG activity with increasing concentrations, while DNMT3A R635W affected TDG activity to a lesser extent. Importantly, wildtype DNMT3A only overcomes the negative effects of mutant DNMT3A on TDG activity at high concentration implying a dominant negative effect of mutant DNMT3A. We subsequently analyzed a larger cohort of AML cases. Targeted sequencing of 750 AML cases and public data from the Cancer Genome Atlas revealed a specific AML subgroup characterized by biallelic DNMT3A mutations, with concurrent TET2, IDH1 or IDH2 mutations, but lacking NPM1 mutations. Our data suggest that impairment of the AOAR pathway combined with the loss of wildtype DNMT3A attenuates TDG activity and greater CpG mutability (Figure 1B). Notably, multivariate analysis revealed that biallelic DNMT3A mutations serve as an independent marker for poor prognosis (p=3.89x10-5). In summary, these studies provide strong evidence for a novel mechanism by which mutant DNMT3A enhances CpG mutagenesis through attenuation of the DNA glycosylase TDG, frequently in combination with AOAR pathway impairment, a mutational pattern frequently observed in AML. Therefore preleukemic mutations in CHIP, like those frequently observed in DNMT3A, could play a pivotal role by increasing the likelihood of acquiring crucial secondary genetic events by attenuating DNA repair at CpGs. Disclosures No relevant conflicts of interest to declare.

DNA methylation: from model plants to vegetable crops

2021 ◽  
Author(s):  
Wen-Feng Nie
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Developmental Process ◽  
Epigenetic Modifications ◽  
Dna Demethylation ◽  
Leafy Vegetables ◽  
Vegetable Crops ◽  
Human Beings ◽  
Horticultural Crops ◽  
Active Dna Demethylation

As a subgroup of horticultural crops, vegetable food is a kind of indispensable energy source for human beings, providing necessary nutritional components including vitamins, carbohydrates, dietary fiber, and active substances such as carotenoids and flavonoids. The developmental process of vegetable crops is not only regulated by environmental stimulations, but also manipulated by both genetic and epigenetic modifications. Epigenetic modifications are composed by several regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. Among these modifications, DNA methylation functions in multiple biological pathways ranging from fundamental development to environmental stimulations by mediating transcriptomic alterations, resulting in the activation or silencing of target genes. In recent years, intensive studies have revealed that DNA methylation is essential to fruit development and ripening, indicating that the epigenome of fruit crops could be dynamically modified according to the specific requirements in the commercial production. Firstly, this review will present the mechanisms of DNA methylation, and update the understanding on active DNA demethylation in Arabidopsis thaliana. Secondly, this review will summarize the recent progress on the function of DNA methylation in regulating fruit ripening. Moreover, the possible functions of DNA methylation on controlling the expansion of edible organs, senescence of leafy vegetables, and anthocyanin pigmentation in several important vegetable crops will be discussed. Finally, this review will highlight the intractable issues that need to be resolved in the application of epigenome in vegetable crops, and provide perspectives for the potential challenges in the further studies.

Global DNA Demethylation During Physiological Erythropoiesis In Vivo

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2083-2083 ◽  
Author(s):  
Jeffrey R Shearstone ◽  
Ramona Pop ◽  
Merav Socolovsky
Keyword(s):  
Dna Methylation ◽  
Dna Replication ◽  
Methylation Level ◽  
Genomic Dna ◽  
Terminal Differentiation ◽  
Significant Loss ◽  
Dna Demethylation ◽  
Erythroid Terminal Differentiation ◽  
Genome Wide ◽  
Erythroid Maturation

Abstract Abstract 2083 In the mammalian genome cytosine residues that are followed by guanine (5’-CpG-3’ dinucleotides) are frequently methylated, a modification that is associated with transcriptional silencing. Two genome-wide waves of demethylation, in primordial germ cells and in the early pre-implantation embryo, erase methylation marks and are each followed by de novo methylation, setting up a pattern subsequently inherited throughout development [1]. While no global methylation changes are thought to occur during further somatic development, methylation does alter at gene-specific loci, contributing to tissue-specific patterns of gene expression. We set out to study dynamic changes in DNA methylation during erythropoiesis. We used flow cytometry and the cell surface markers CD71 and Ter119 to subdivide freshly isolated fetal liver cells into a developmental sequence of six subsets, from the least mature Subset 0 (S0), to the most mature Subset 5 (S5) [2]. We measured DNA methylation in genomic DNA prepared from freshly sorted S0 to S5 cells. Surprisingly, we found that demethylation at the erythroid-specific β-globin locus control region (LCR) was coincident with progressive genome-wide methylation loss. Both global demethylation as well as demethylation at the β-globin LCR began with the upregulation of CD71 at the onset of erythroid terminal differentiation, and continued with erythroid maturation, with global hypomethylation persisting during enucleation. We employed several distinct methodologies to measure global DNA methylation level. Using Enzyme-Linked Immunosorbent Assay (ELISA), we found that genomic DNA isolated from increasingly mature erythroblasts had progressively reduced binding to a 5-methylcytosine-specific antibody. We also used the LUminometric Methylation Assay (LUMA) to compare the genome-wide cleavage of CCGG sites by each of the isoschizomers HpaII and MspI, which are methylation sensitive and insensitive, respectively. Both the ELISA and LUMA assays showed a global, progressive and significant loss of DNA methylation with erythroid differentiation: 70% of CpG dinucleotides genome-wide were methylated in S0, decreasing to 40–50% by S4/5 (p<0.01). Further, using pyrosequencing of bisulfite-converted DNA, we found a similar decrease in CpG methylation in the promoters of genes whose transcription is silenced with erythroid maturation, notably PU.1 and Fas. To characterize the global loss in methylation further, we examined the status of imprinted genes and of repetitive transposable elements, since both represent genetic loci that are usually stably and highly methylated in somatic cells. We found loss of methylation in imprinted loci, including PEG3 and the H19 Differentially Methylated Region (DMR). We also found a significant loss of methylation at the Long Interspersed Nuclear Element (LINE-1), a repetitive retrotransposon, whose methylation level decreased from over 90% in S0 cells, to 70% in S4/5. Mechanistically, global demethylation was associated with a rapid decline in the DNA methyltransferases DNMT3a and DNMT3b. However, exogenous re-expression of these enzymes in vitro was not sufficient to reverse the process. Both global and erythroid-specific demethylation required rapid DNA replication, triggered with the onset of erythroid terminal differentiation. We were able to slow down demethylation quantitatively by slowing down the rate of DNA replication with aphidicolin, an inhibitor of DNA polymerase α. Global loss of DNA methylation was not associated with a global increase in transcription, as determined by GeneChip analysis, nor was it associated with increased transcription of the LINE-1 retrotransposon. We propose that global demethylation is a consequence of global cellular mechanisms required for the rapid demethylation and induction of β-globin and other erythroid genes. Our findings suggest mechanisms of global demethylation in development and disease, and show that contrary to previously held dogma, DNA demethylation occurs globally during physiological somatic cell differentiation. References: 1. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293: 1089–1093. 2. Socolovsky M, Murrell M, Liu Y, Pop R, Porpiglia E, et al. (2007) Negative Autoregulation by FAS Mediates Robust Fetal Erythropoiesis. PLoS Biol 5: e252. Disclosures: No relevant conflicts of interest to declare.

scholarly journals DNA Demethylation Pathways: Recent Insights

2013 ◽  
Vol 5 ◽  
pp. GEG.S12143 ◽  
Author(s):  
Cong-jun Li
Keyword(s):  
Dna Methylation ◽  
Mammalian Cells ◽  
De Novo ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Sequencing Technologies ◽  
Active Dna Demethylation ◽  
Mammalian Genomes ◽  
Genome Context

DNA methylation is a major epigenetic regulatory mechanism for gene expression and cell differentiation. Until recently, it was still unclear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether or not active demethylating activity is involved. Even the role of molecules and the mechanisms underlying the processes of active demethylation itself is blurred. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within a distinct genome context, such as the promoters, exons, or imprinted control regions. This review summarizes recent insights on the dynamic nature of DNA methylation and demethylation, as well as the mechanisms regulating active DNA demethylation in mammalian cells, which have been fundamental research interests in the field of epigenomics.

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