The Ski protein family is required for MeCP2-mediated transcriptional repression.
Open accessAbstract
DNA methylation is essential for development in the mouse and plays an important role in inactivation of the X chromosome and genomic imprinting. MeCP2 is the founder member of a family of methyl-CpG-binding proteins. MeCP2 directly binds to the co-repressor mSin3, which interacts with class I histone deacetylase, recruiting them to methyl-CpG regions to suppress transcription. Here, we report that MeCP2 directly binds to two co-repressors, c-Ski and N-CoR, in addition to mSin3A, and that the c-Ski, which is encoded by the c-ski proto-onocogene, is required for MeCP2-mediated transcriptional repression. The two regions of c-Ski, including the C-terminal coiled-coil region, interact with the transcriptional repression domain in the center of the MeCP2 molecule. The immunostaining signals for c-Ski and MeCP2 overlap in the nuclear heterochromatin region, suggesting the co-localization of the two proteins. The degree of transcriptional repression mediated by a Gal4-MeCP2 fusion protein was abrogated by overexpression of the putative dominant negative form of c-Ski. Furthermore, injection of antibodies against c-Ski and Sno almost completely abolished the transcriptional repression mediated by the Gal4-MeCP2 fusion protein. These results suggest that the ski gene family is involved in methyl CpG-mediated transcriptional repression.
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MeCP2 binds to the NCoR1/SMRT co-repressor complex.
“In 2001, Kokura et al. [83] first demonstrated that MeCP2 binds to the NCoR1/SMRT co-repressor complex.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [83]
The binding-results section reports that purified MeCP2 binds directly to an N-CoR fragment. The Discussion describes the N-CoR/SMRT complex but says only that separate co-repressor complexes may associate with MeCP2; it does not demonstrate binding to the intact N-CoR/SMRT complex or to SMRT. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere is evidence that NCoR can interact directly with methyl-binding proteins or indirectly via its interaction with the Sin3 corepressor complex.
“Although numerous corepressors have been identified that interact with methyl-binding proteins, there is evidence that NCoR can interact directly with methyl-binding proteins (22)(23)(24) or indirectly via its interaction with the Sin3 corepressor complex (36).”
From The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior (2010) · cites this paper as [24]
NCoR can also repress gene expression via its interactions with methyl-binding proteins, such as Kaiso and MeCP2.
“Given that NCoR disruption increases juvenile anxiety-like behavior in both males and females, it is important to consider that NCoR can also repress gene expression via its interactions with methyl-binding proteins, such as Kaiso (22) and MeCP2 (23,24).”
From The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior (2010) · cites this paper as [24]
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- Authors
- Kokura, K., Kaul, S. C., Wadhwa, R., Nomura, T., Khan, M. M., Shinagawa, T., Yasukawa, T., Colmenares, C., & Ishii, S.
- Affiliations
- RIKEN (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- Japan Science and Technology Agency (JP)
- Cleveland Clinic (US)
- Corresponding author
- Ishii, Shunsuke
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 276
- Issue
- 36
- Pages
- 34115-34121
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2021284263
- Cited by
- 222
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 7 · 2016: 11 · 2015: 10 · 2014: 3 · 2013: 17 · 2012: 14
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 30728)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- MeCP2, c-Ski, NCoR, mSin3A, transcriptional repression, DNA methylation, methyl-CpG binding proteins, corepressors, histone deacetylase, coiled-coil domain, heterochromatin, dominant negative effect, X chromosome inactivation, genomic imprinting
- MeSH terms
- Cell Line, Cell Nucleus, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Gene Expression Regulation, Genes, Dominant, Multigene Family, Glutathione Transferase, Heterochromatin, Humans, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Repressor Proteins, Transcription, Genetic, Blotting, Western, Protein Structure, Tertiary, DNA, Complementary, CpG Islands, DNA Methylation, Methyl-CpG-Binding Protein 2
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