Base-Resolution Analyses of Sequence and Parent-of-Origin Dependent DNA Methylation in the Mouse Genome

Xie, Wei; Barr, Cathy L.; Kim, Audrey; Yue, Feng; Lee, Ah Young; Eubanks, James H.; Dempster, Emma; Ren, Bing

doi:10.1016/j.cell.2011.12.035

Cited by 496 publications

(541 citation statements)

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“…15). These studies indicate that the mCG landscape is generally similar in postnatal neurons and other cell types, so that intergenic regions and repeat DNA contain high levels of mCG, and active regulatory elements (e.g., enhancers and promoters depletion) are depleted of mCG (8,9,(16)(17)(18). Thus, in neurons, as in other cell types, mCG is thought to silence the transcription of repeats across the genome and to regulate gene expression by promoting transcriptional repression (19,20).…”

mentioning

confidence: 95%

“…Here, the results of base-resolution methylation mapping from the brain provide a clue to explain these apparently incongruous findings. These recent methylome analyses report that strong bias for mCH occurs in the CA context [∼60% of mCH appears as CA methylation (mCA)], with several studies identifying a longer preferred sequence than just mCA (8,9,17). In this regard, the oligonucleotide probe used in the recent study by Guo et al (9) included mCH with the preferred sequence context, suggesting that MeCP2 binding to mCH might display sequence preferences.…”

Section: Binding Of Mecp2 To the Brain-specific Methylomementioning

confidence: 99%

“…Dnmt3a and Dnmt3b are both highly expressed in ES cells, whereas Dnmt3a, but not Dnmt3b, is highly expressed in neurons (8,14). Perhaps as a consequence of the differential expression of these de novo DNA methyltransferases and the mechanisms by which they are targeted to the genome, the predominant form of mCH in ES cells occurs within the context of the CAG trinucleotide, whereas in neurons mCH occurs largely within the CAC trinucleotide (8,9,17,26,27). The differential distribution and sequence context of mCH may have important implications for readers of DNA methylation and whether they function as activators or repressors of gene expression.…”

mentioning

confidence: 99%

“…Indeed, mCH is nearly absent from nonneuronal adult somatic cells (9,21). However, with the application of whole-genome single-base-resolution DNA methylation profiling methods that use precise controls to distinguish the background nonconverted cytosines that remain after bisulfite treatment from true low-level methyl-cytosines (15), significant levels of mCH were detected, first in ES cells and then in the adult brain (16,17). Subsequent analysis of NeuN + neurons has shown that mCH is specifically enriched in neurons relative to other cell types (8,9).…”

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confidence: 99%

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Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Kinde

Gabel

Gilbert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

216

198

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DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.M ethylation of cytosines at the carbon 5 position (5-methylcytosine, mC) constitutes the most common covalent modification of vertebrate genomic DNA. Traditionally, cytosine methylation in vertebrate genomes has been viewed as largely restricted to CpG dinucleotide (CG) sequences, providing a stable epigenetic mark that mediates long-term transcriptional silencing. Indeed, 60-90% of all CGs are methylated in mammalian genomes, and CG methylation (mCG) has been shown to play critical roles in genomic imprinting, X-chromosome inactivation, cellular differentiation, and development (1). In addition, the disruption of cellular DNA methylation patterns has been linked to human disease, including multiple cancers (2, 3).Evidence that DNA methylation has a uniquely important role in the brain emerged almost two decades ago with the discovery of the prominent methyl-DNA-binding protein, methyl-CpG-binding protein 2 (MeCP2), and the later identification that mutations in MeCP2 give rise to the X-linked neurological disorder Rett syndrome (RTT) (4-6). Subsequent studies also have identified neurodevelopmental disorders associated with mutations in DNA methyltransferases (7), suggesting that both the enzymatic "writers" of DNA methylation patterns and the "readers" of these marks have important roles in the brain. In this context, new studies from several laboratories have uncovered extensive cytosine modification in the brain beyond mCG. Non-CG methylation (CH methylation or mCH, in which H = A, C, or T) is now appreciated to accumulate in the human and mouse brain postnatally, reaching levels similar to that of mCG in the neuronal genome (8, 9). Moreover, oxidation of mC by the ten-eleven translocation (Tet) family of dioxygenases leads to the selective accumulation of 5-hydroxymethylcytosine (hmC) in the adult brain, together with its more highly oxidized derivatives 5-formylcytosine and 5-carboxylcytosine (10, 11). This finding suggests that hmC may act as an intermediate in an active DNA demethylation pathway, though growing evidence also suggests that hmC may serve as a stable neuronal epigenetic mark in its own right (12).The discovery of these previously unidentified brain-enriched forms of DNA methylation provides...

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mentioning

confidence: 95%

Section: Binding Of Mecp2 To the Brain-specific Methylomementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Kinde

Gabel

Gilbert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

216

198

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“…For instance, non-CpG methylation is particularly abundant in mouse and human brain tissue. 17,18 Analysis of human adult brain tissue (specifically the dorsolateral prefrontal cortex of healthy donors) showed that 666/2466 non-CpG dinucleotides tested across the genome were methylated across all 24 individuals tested. 18 An interesting characteristic of non-CpG methylation is that it can occur in a variety of sequence contexts, but is most frequently found at CpA dinucleotides.…”

Section: Evidence For Non-cpg Methylation In Mammalian Cellsmentioning

confidence: 99%

The evidence for functional non-CpG methylation in mammalian cells

2014

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Genomic Imprinting at the Transcriptional Level

Brandão

Rocha

2018

Encyclopedia of Life Sciences

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Genomic imprinting is an epigenetic mechanism of gene regulation causing genes to be expressed from only one of the two parentally inherited chromosomes in mammals. Imprinted genes often cluster in large chromosomal domains and their expression is regulated by cis ‐acting imprinting control regions. These regions carry an epigenetic imprint, mostly in the form of deoxyribonucleic acid methylation, laid down during gametogenesis, when the two genomes are separated. Regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers or cis ‐regulation induced by long noncoding RNAs. Aberrant expression of imprinted genes leads to human pathologies characterised by mental, developmental and metabolic abnormalities. Imprinting errors are also often seen in stem cells, including induced pluripotent stem cells and affect their physiology and pluripotent potential. For these reasons, genomic imprinting remains a crucial model for understanding the epigenetic influence on transcriptional activity and repression. Key Concepts A subset of genes in the mammalian genome (<1%) known as imprinted genes are expressed exclusively from one of the two parental alleles. Imprinted genes are involved in foetal growth and placental development in the uterus, as well as brain function and metabolism in adults. Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are coordinatively regulated. Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alleles during gametogenesis. DNA methylation is the bona fide imprint mark at ICRs, but chromatin modifications, such as H3K27me3, also serve as an imprint mark at transient and/or placental‐specific ICRs. Methylation imprints are established in the parental germ line, resist the wave of DNA demethylation after fertilisation and are erased before resetting in the germ line according to the sex. Insulation of common enhancers by the methylated sensitive protein Ctcf explains the imprinting regulation at the Igf2/H19 region. Silencing of genes in cis by long noncoding RNAs (lncRNAs) explains the imprinting regulation of, at least, three clusters through transcription interference and recruitment of chromatin modifiers. Deregulation of genomic imprinting can cause imprinted disorders in humans, which exhibit parent of origin effects in their pattern of inheritance. Imprinting defects occur in stem cells and during somatic reprogramming into induced pluripotent stem cells (iPSCs) affecting their pluripotency and harness their potential clinical applications.

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Base-Resolution Analyses of Sequence and Parent-of-Origin Dependent DNA Methylation in the Mouse Genome

Cited by 496 publications

References 75 publications

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

The evidence for functional non-CpG methylation in mammalian cells

Genomic Imprinting at the Transcriptional Level

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