MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system
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The high level of 5-hydroxymethylcytosine (5hmC) present in neuronal genomes suggests that mechanisms interpreting 5hmC in the CNS may differ from those present in embryonic stem cells. Here, we present quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo. We report that 5hmC is enriched in active genes and that, surprisingly, strong depletion of 5mC is observed over these regions. The contribution of these epigenetic marks to gene expression depends critically on cell type. We identify methyl-CpG-binding protein 2 (MeCP2) as the major 5hmC-binding protein in the brain and demonstrate that MeCP2 binds 5hmC- and 5mC-containing DNA with similar high affinities. The Rett-syndrome-causing mutation R133C preferentially inhibits 5hmC binding. These findings support a model in which 5hmC and MeCP2 constitute a cell-specific epigenetic mechanism for regulation of chromatin structure and gene expression.
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5hmC in the nervous system is associated with actively transcribed genes and recognized by MeCP2, which is inactivated in Rett syndrome.
“5hmC in the nervous system is associated with actively transcribed genes and is recognized by the histone-reader protein MeCP2, which is mutationally inactivated in the neurological disorder of Rett syndrome (Mellén et al., 2012).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Mellén et al., 2012
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- Authors
- Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S., & Heintz, N.
- Affiliations
- Howard Hughes Medical Institute (US)
- Rockefeller University (US)
- Corresponding author
- Heintz, Nathaniel
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 151
- Issue
- 7
- Pages
- 1417-1430
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3653293
- OpenAlex
- W2113486281
- Cited by
- 943
- References
- 56
- Citations by year
- 2026: 27 · 2025: 35 · 2024: 45 · 2023: 38 · 2022: 45 · 2021: 46 · 2020: 60 · 2019: 60 · 2018: 70 · 2017: 97 · 2016: 105 · 2015: 94 · 2014: 121 · 2013: 93
- FWCI
- 39.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (P50MH090963, MH090963)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- 5-hydroxymethylcytosine, 5-methylcytosine, MeCP2, Rett syndrome, DNA methylation, epigenetic regulation, gene expression, chromatin accessibility, neuronal cell types, brain, chromatin structure
- MeSH terms
- Animals, Cerebellum, Chromatin, Cytosine, Humans, Neuroglia, Neurons, Purkinje Cells, Rett Syndrome, Mice, Knockout, Epigenesis, Genetic, 5-Methylcytosine, Mice, Methyl-CpG-Binding Protein 2
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