DNA methylation in the gene body influences MeCP2-mediated gene repression
Open accessAbstract
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.
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The Mecp2 correlation supports a model in which MECP2 represses gene expression by binding methylated nucleotides, creating a stoichiometric requirement for increased Mecp2 expression in cells with higher overall methylation.
“supporting a model in which MECP2 represses gene expression by specifically binding to methylated nucleotides (Kinde et al., 2016), creating a stoichiometric requirement for increased Mecp2 expression in cells with higher overall methylation levels.”
From Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity (2019) · cites this paper as Kinde et al., 2016
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- Authors
- Kinde, B., Wu, D. Y., Greenberg, M. E., & Gabel, H. W.
- Affiliations
- Harvard University (US)
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-12-13
- Volume
- 113
- Issue
- 52
- Pages
- 15114-15119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5206576
- OpenAlex
- W2565629561
- Cited by
- 118
- References
- 30
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 11 · 2023: 14 · 2022: 6 · 2021: 17 · 2020: 8 · 2019: 16 · 2018: 18 · 2017: 5
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rett syndrome research trust (NA)
- HHS | National Institutes of Health (5R01NS048276-12, T32GM007753)
- Howard Hughes Medical Institute (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, MeCP2, Rett syndrome, gene body methylation, gene repression, transcriptional repression, RNA polymerase elongation, methyl-CpG binding proteins, neurons
- MeSH terms
- Animals, Binding Sites, Brain, Gene Expression Regulation, Humans, Mutation, Neurons, Protein Binding, Repressor Proteins, Transcription, Genetic, Rett Syndrome, Gene Expression, Mice, Knockout, CpG Islands, DNA Methylation, Gene Expression Profiling, Mice, Methyl-CpG-Binding Protein 2
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