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

Benyam Kinde, Dennis Y. Wu, Michael E. Greenberg, Harrison W. Gabel

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 comparingwild-type andMeCP2-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 ofmCA 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 extendedmegabase-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 genebody 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.

Original languageEnglish
Pages (from-to)15114-15119
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number52
DOIs
StatePublished - Dec 27 2016

Keywords

  • DNA methylation
  • MeCP2
  • Rett syndrome
  • Transcription

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