DNA methylation in the gene body influences MeCP2-mediated gene repression

Abstract

Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein gene (MECP2). MeCP2 is a methyl-cytosine binding protein that is proposed to function as a transcriptional repressor. However, multiple gene expression studies comparing wild-type and MeCP2-deficient neurons have failed to identify gene expression changes consistent with loss of a classical transcriptional repressor. Recent work suggests that one function of MeCP2 in neurons is to temper the expression of the longest genes in the genome by binding to methylated CA dinucleotides (mCA) within transcribed regions of these genes. Here we explore the mechanism of mCA and MeCP2 in fine tuning the expression of long genes. We find that mCA is not only highly enriched within the body of genes normally repressed by MeCP2, but also enriched within extended megabase-scale regions surrounding MeCP2-repressed genes. Whereas enrichment of mCA exists in a broad region around these genes, mCA together with mCG within gene bodies appears to be the primary driver of gene repression by MeCP2. Disruption of methylation at CA sites within the brain results in depletion of MeCP2 across genes that normally contain a high density of gene-body mCA. We further find that the degree of gene repression by MeCP2 is proportional to the total number of methylated cytosine MeCP2 binding sites across the body of a gene. These findings suggest a model in which MeCP2 tunes gene expression in neurons by binding within the transcribed regions of genes to impede the elongation of RNA polymerase.

MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain

“…In addition the results fit with the conclusions of Gabel and colleagues [26] who found repression of long genes by MeCP2. They furthermore accord with a previously published study indicating that transcriptional repression by MeCP2 depends upon domains of DNA methylation, notably in gene bodies [45]. Although we emphasize the correlation with binding site density per unit of DNA length, it is possible that the absolute number of binding sites per gene also contributes to the MeCP2 response.…”

Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States

“…These findings collectively suggest that mCA contributes to the fine-tuning of genes, including those with critical neuronal functions, in a neuronal subtype-specific manner at least in part by differentially recruiting MECP2 to neuronal gene bodies. Once bound to mCA, MECP2 appears to restrain gene transcription to a level of expression that is directly correlated with the number of mCA marks/MECP2 binding sites per gene thus preferentially regulating some of the longest genes in the genome (Kinde et al, 2016; Lagger et al, 2017; Sugino et al, 2014). We note that the long genes that are up-regulated when MeCP2 function is disrupted are typically lowly expressed in wild type neurons (Figure S7E).…”

Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic

“…Evidence from in vitro (11,12) and mouse models (13,14) suggests that MeCP2 can mediate DNA methylation-dependent transcriptional inhibition. Transcriptional changes in mouse brain when MeCP2 is absent or over-expressed are relatively subtle but widespread (15)(16)(17), and the molecular mechanisms underlying these changes are unknown.…”