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Journal ArticleDOI

MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system

TL;DR: In this paper, a quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo is presented.
Abstract: SUMMARY The high level of 5-hydroxymethylcytosine (5hmC) present in neuronal genomes suggests that mechanisms interpreting 5hmC in the CNS may differ from those present in embryonic stem cells. Here, we present quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo. We report that 5hmC is enriched in active genes and that, surprisingly, strong depletion of 5mC is observed over these regions. The contribution of these epigenetic marks to gene expression depends critically on cell type. We identify methyl-CpG-binding protein 2 (MeCP2) as the major 5hmC-binding protein in the brain and demonstrate that MeCP2 binds 5hmC- and 5mC-containing DNA with similar high affinities. The Rett-syndrome-causing mutation R133C preferentially inhibits 5hmC binding. These findings support a model in which 5hmC and MeCP2 constitute a cell-specific epigenetic mechanism for regulation of chromatin structure and gene expression.

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Citations
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Journal ArticleDOI
09 Aug 2013-Science
TL;DR: The results extend the knowledge of the unique role of DNA methylation in brain development and function, and offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits.
Abstract: DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.

1,629 citations


Cites background or result from "MeCP2 binds to 5hmc enriched within..."

  • ...hmC accumulates during early postnatal brain development in mice (31, 32), becoming enriched in highly expressed genes (33)....

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  • ...Overall, transcriptional activity is associated with intragenic hmCG enrichment, as reported (33), with in utero establishment of adult hmCG patterns for cell type–specific genes and loss of hmC enrichment associated with developmentally coupled transcriptional down-regulation....

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  • ...These constitutively highly expressed genes enriched for neuronal function also show extensive intragenic mCH hypomethylation in neurons in contrast to glia (box 3), and they are enriched for hmCG (box 4) as previously described (32, 33)....

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  • ...Our base-resolution analysis of hmC using TAB-Seq revealed that intragenic and global hmCG levels are largely equivalent between chromosomes, whereas hmCG/CG is 22% lower on the male ChrX, consistent with previous reports from enrichment based detection of hmC (32, 33) (Fig....

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Journal ArticleDOI
TL;DR: This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression, and discusses some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.
Abstract: Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.

1,365 citations

Journal ArticleDOI
24 Oct 2013-Nature
TL;DR: Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
Abstract: DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.

1,336 citations

Journal ArticleDOI
TL;DR: Recent advances in biochemical and structural studies have revealed mechanistic insights into how TET and TDG mediate active DNA demethylation and many regulatory mechanisms of this process have been identified.
Abstract: A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.

1,012 citations

Journal ArticleDOI
28 Feb 2013-Cell
TL;DR: Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.

897 citations


Cites background from "MeCP2 binds to 5hmc enriched within..."

  • ...…binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation....

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References
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Journal ArticleDOI
TL;DR: It is concluded that H1 has no significant preference for binding to naked methylated DNA and potential cooperative interaction of H1 with polynucleosomal complexes is not enhanced by the presence of DNA methylation.

46 citations


"MeCP2 binds to 5hmc enriched within..." refers methods in this paper

  • ...To confirm this result, similar affinity purifications were repeated from brain nuclear extracts of wild-type (WT) and Mecp2 knockout (KO) animals using beads coated with DNA containing C or 5hmC, and assayed using Southwestern analysis (Campoy et al., 1995)....

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Journal ArticleDOI
06 Oct 2011-Neuron
TL;DR: The study suggests a prominent role for MeCP2 in the regulation of global chromatin state in vivo and revised understanding of how activity-dependent MeCP1 phosphorylation regulates distinct aspects of brain development and circuit function.

13 citations


"MeCP2 binds to 5hmc enriched within..." refers background in this paper

  • ..., 1999) or posttranslational modification (Rutlin and Nelson, 2011; Gonzales et al., 2012), will be cell type and circuit specific....

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  • ...…been shown to occur in response to a variety 1424 Cell 151, 1417–1430, December 21, 2012 ª2012 Elsevier Inc. of stimuli (Chen et al., 2003; Tao and Wu, 2009; Rutlin and Nelson, 2011; Adkins and Georgel, 2011; Gonzales et al., 2012) could alter its substrate specificity and downstream functions....

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  • ...…each cell type, the phenotypic consequences of changes in the function of MeCP2, whether as a result of mutation (Adkins and Georgel, 2011; Tao andWu, 2009; Amir et al., 1999) or posttranslational modification (Rutlin and Nelson, 2011; Gonzales et al., 2012), will be cell type and circuit specific....

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  • ...of stimuli (Chen et al., 2003; Tao and Wu, 2009; Rutlin and Nelson, 2011; Adkins and Georgel, 2011; Gonzales et al., 2012) could alter its substrate specificity and downstream functions....

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Book ChapterDOI
TL;DR: With the development of new technologies, deciphering the role of MeCP2 on a genome-wide scale is important for understanding of the RTT disease mechanisms.
Abstract: Mutations of MECP2 (methyl-CpG binding protein 2) cause Rett syndrome (RTT). Mouse genetics studies have demonstrated that the lack of functional MeCP2 in the central nervous system leads to RTT-like symptoms, which could be reversed upon MeCP2 restoration. MeCP2 recognizes methylated CpG dinucleotides and may interact with other chromatin remodeling proteins. Although traditionally thought to be a transcription repressor, MeCP2 may also be involved in transcription activation. With the development of new technologies, deciphering the role of MeCP2 on a genome-wide scale is important for understanding of the RTT disease mechanisms.

10 citations


"MeCP2 binds to 5hmc enriched within..." refers background in this paper

  • ...…that have been shown to occur in response to a variety 1424 Cell 151, 1417–1430, December 21, 2012 ª2012 Elsevier Inc. of stimuli (Chen et al., 2003; Tao and Wu, 2009; Rutlin and Nelson, 2011; Adkins and Georgel, 2011; Gonzales et al., 2012) could alter its substrate specificity and downstream…...

    [...]

  • ...of stimuli (Chen et al., 2003; Tao and Wu, 2009; Rutlin and Nelson, 2011; Adkins and Georgel, 2011; Gonzales et al., 2012) could alter its substrate specificity and downstream functions....

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