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MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome
Open accessAbstract
Significance: Decades of research have not deciphered the mechanism by which methyl-CpG binding protein 2 (MeCP2) regulates transcription and why Rett symptoms manifest 1 to 2 y after birth. We hypothesized that the temporal dynamics of MeCP2 binding might provide an answer. We developed mice with an EGFP-tagged MeCP2 allele to identify high-resolution MeCP2 binding profiles in the adult mouse brain. Using genomic binding profiles, methylation maps, and mRNA deep-sequencing data, we found MeCP2 binds to non-CG methylation (mCH, not mCG) to regulate expression of genes altered in mouse models of MeCP2 disorders. These data and the parallel timing of mCH and MeCP2 postnatal accumulation suggest MeCP2 binds mCH as neurons mature to regulate gene expression, offering an explanation for the delayed onset of Rett.
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“A previous study showed that the binding of MeCP2 to non-CpG methylates DNA sequences is critical for BDNF expression. This process influenced the onset timing for Rett syndrome.64”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [64]
In the citing paper
“In neurons, intragenic 5mCH quantitatively modulates gene expression by interacting with MECP2 and recruiting NCoR corepressor complex to chromatin (37–40).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [38]
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Metadata
- Authors
- Chen, L., Chen, K., Lavery, L. A., Baker, S. A., Shaw, C. A., Li, W., & Zoghbi, H. Y.
- Affiliations
- Texas Children's Hospital (US)
- Dan L Duncan Comprehensive Cancer Center (US)
- Department of Molecular and Human Genetics,
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-04-13
- Volume
- 112
- Issue
- 17
- Pages
- 5509-5514
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4418849
- OpenAlex
- W2166288018
- Cited by
- 301
- References
- 31
- Citations by year
- 2026: 20 · 2025: 21 · 2024: 25 · 2023: 20 · 2022: 23 · 2021: 23 · 2020: 28 · 2019: 21 · 2018: 24 · 2017: 38 · 2016: 37 · 2015: 13
- FWCI
- 25.51
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-04-27)
- 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
- Howard Hughes Medical Institute
- National Human Genome Research Institute (R01HG007538, HG007538)
- National Institute of Neurological Disorders and Stroke (T32NS043124, R01NS057819)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092, P30HD024064)
- 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
- MeCP2, Rett syndrome, non-CG DNA methylation, neuronal gene expression, transcriptional regulation, DNA methylation, brain-derived neurotrophic factor, brain development, delayed symptom onset, epigenetic regulation
- MeSH terms
- Animals, Disease Models, Animal, DNA, Gene Expression Regulation, Male, Mice, Transgenic, Neurons, Transcription, Genetic, Rett Syndrome, DNA Methylation, Brain-Derived Neurotrophic Factor, Mice, Methyl-CpG-Binding Protein 2
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