Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain

Wen, Lu; Li, Xianlong; Yan, Liying; Tan, Yuexi; Li, Rong; Zhao, Yangyu; Wang, Yan; Xie, Jingcheng; Zhang, Yan; Song, Chun-Xiao; Yu, Miao; Liu, Xiaomeng; Zhu, Ping; Li, Xiaoyu; Hou, Yu; Guo, Hongshan; Wu, Xinglong; He, Chuan; Li, Ruiqiang; Tang, Fuchou

doi:10.1186/gb-2014-15-3-r49

Cited by 249 publications

(268 citation statements)

References 48 publications

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“…In addition to specific sites of intragenic enrichment for hmCG, an accumulation of hmCG occurs broadly across intergenic regions of the neuronal genome. Thus, in stark contrast to other cell types, such as ES cells, in which hmCG is localized primarily to active regulatory elements, in neurons, even intergenic regions contain substantial levels of hmCG (20-30%) (8,33).…”

mentioning

confidence: 88%

“…Although hmCG is present at appreciable levels in neurons, TLC and genome-wide bisulfite sequencing analyses conducted to date suggest that hmCA, if it exists, is present in the neuronal genome at low levels (8,29,33). Thus, oxidative conversion of mC to hmC may primarily influence the distribution of MeCP2 molecules in neuronal chromatin by decreasing the binding affinity of MeCP2 at preexisting mCG sites.…”

Section: Binding Of Mecp2 To the Brain-specific Methylomementioning

confidence: 99%

“…Current data indicate that hmC is substantially enriched in CNS neurons compared with other cell types, with hmC levels being ∼10-fold greater in the brain than in ES cells (31,32) and with CG hydroxymethylation (hmCG) accounting for 25% and 40% of all modified CG dinucleotides in the frontal cortex and cerebellum, respectively (8,29,33). Brain hmCG levels increase postnatally in parallel with mCH, with an approximately fourfold increase in abundance within the first 6 weeks after birth (8,34).…”

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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: 88%

Section: Binding Of Mecp2 To the Brain-specific Methylomementioning

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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“…An increasing number of studies have reported associations between development and aging and DNA methylation profiles in different brain regions, blood, muscle, saliva, and other tissues, including both cross-sectional and longitudinal analyses [89][90][91][92][93][94]. Importantly, these types of studies have not all accounted for the confounding effects of having samples with varying cellular compositions [95].…”

Section: Development and Agingmentioning

confidence: 99%

“…Point mutation in a primate-specific repeat (L1PA8) within an Alu element, which is embedded in a brain expressed lncRNA, mediates disease [23] Rett syndrome MeCP2 represses L1 retrotransposition in neuronal cells and, in reprogrammed cells from Rett syndrome patient tissues, L1 activity is increased [47] Schizophrenia L1 copy number is increased in neurons from patient-derived prefrontal cortex specimens, and brain-specific L1 insertions seem to preferentially target genes involved in synaptic function or linked to schizophrenia [46] ATM = ataxia telangiectasia mutated; SVA = SINE-VNTR-Alu; 3′-UTR = 3′-untranslated region; lncRNA = long noncoding RNA; MeCP2 = methylCpG-binding protein 2; L1 = long interspersed element 1 during development and aging [89][90][91][92][93][94]. Moreover, it is notable that methylation marks measured in easily accessible peripheral tissues, such as blood, can serve as reliable surrogates for those present in brain for certain subsets of genes [89].…”

Section: Diseasementioning

confidence: 99%

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

Qureshi

Mehler

2014

Neurotherapeutics

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There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. The emerging field of epigenetics is also providing further insights into these mechanisms. Here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology-which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other healthrelated phenotypes, and disease states-and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.

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