MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system
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...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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...…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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"MeCP2 binds to 5hmc enriched within..." refers background in this paper
...throughout the genome plays an important role in transcriptional repression (Guy et al., 2011)....
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...…and the Organization of Neuronal Chromatin Evidence from a wide variety of studies supports a general model in which MeCP2 binding to 5mC at CpG dinucleotides cember 21, 2012 ª2012 Elsevier Inc. 1425 throughout the genome plays an important role in transcriptional repression (Guy et al., 2011)....
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...Advances in our understanding of the pathophysiology of RTT will require further investigation of this new role for MeCP2 in facilitating gene expression when bound to 5hmC in the context of the traditional repressive functions it elicits upon its binding to 5mC (Guy et al., 2011)....
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...…distribution of 5hmC throughout the transcription unit of highly expressed genes distinguishes this mechanism from the established roles of MeCP2 and other MBD family proteins in the organization of repressive chromatin complexes at promoters and enhancers (Guy et al., 2011; Yildirim et al., 2011)....
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...First, the distribution of 5hmC throughout the transcription unit of highly expressed genes distinguishes this mechanism from the established roles of MeCP2 and other MBD family proteins in the organization of repressive chromatin complexes at promoters and enhancers (Guy et al., 2011; Yildirim et al., 2011)....
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384 citations
"MeCP2 binds to 5hmc enriched within..." refers background in this paper
...…it is approximately 10-fold more abundant in neurons than in some peripheral tissues or embryonic stem (ES) cells (Kriaucionis and Heintz, 2009; Münzel et al., 2010; Szulwach et al., 2011) suggests that 5hmC is a stable epigenetic mark that engages cell-specific mechanisms to carry out its…...
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...The recent discovery of 5-hydroxymethylcytosine (5hmC) in the mammalian genome and the demonstration that it is approximately 10-fold more abundant in neurons than in some peripheral tissues or embryonic stem (ES) cells (Kriaucionis and Heintz, 2009; Münzel et al., 2010; Szulwach et al., 2011) suggests that 5hmC is a stable epigenetic mark that engages cell-specific mechanisms to carry out its functions in the brain....
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289 citations
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...We have not, for example, assessed the influence of activity-dependent mechanisms (Cohen et al., 2011) on the interactions of MeCP2 with 5mC-containing or 5hmC-containing DNA....
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235 citations
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...Consistentwith previous results (Ben-Shachar et al., 2009), the majority of genes whose expression is altered in the cerebellum in response to loss of MeCP2 were downregulated (Figure 6D; Tables S2C and S2D)....
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...Our data support previous genetic studies demonstrating that the consequences of MeCP2 loss in different neural cell types differ both quantitatively and qualitatively (Ben-Shachar et al., 2009), and suggest that the specific biochemical properties of mutant MeCP2 proteins may inform our understanding of their clinical consequences....
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...This model provides a mechanistic explanation for the recent demonstration thatMeCP2can also activate gene expression, as somegenesarebothdownregulatedupon lossofMeCP2 and upregulated in mice with increased Mecp2 gene dosage (Ben-Shachar et al., 2009; Chahrour et al., 2008; Figure 6)....
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...…genetic studies demonstrating that the consequences of MeCP2 loss in different neural cell types differ both quantitatively and qualitatively (Ben-Shachar et al., 2009), and suggest that the specific biochemical properties of mutant MeCP2 proteins may inform our understanding of their…...
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...…is localized within highly nuclease accessible regions (Thambirajah et al., 2012), that loss of MeCP2 can lead to downregulation of expressed genes (Ben-Shachar et al., 2009; this study), and that 5hmC is enriched in the gene bodies of highly expressed genes (Song et al., 2011; this study)…...
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228 citations
"MeCP2 binds to 5hmc enriched within..." refers background in this paper
...For example, it is well documented that patients carrying the R133C mutation have a milder form of RTT that is characterized by delayed onset regression, with improved speech and motor skills (Bebbington et al., 2008)....
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...However, for many other characteristics, including breathing abnormalities, sleep problems, mood disturbances, and epilepsy prevalence, no significant differences are evident between patients bearing R133C or othermutations (Bebbington et al., 2008)....
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