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Cited by 410Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationGenomics and Rare Diseases

Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor

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Lyst, Matthew J, Ekiert, Robert, Ebert, Daniel H, Merusi, Cara, Nowak, Jakub, Selfridge, Jim, Guy, Jacky, Kastan, Nathaniel R +5 more·2013·Nature Neuroscience
DOI 10.1038/nn.3434PMC PMC3786392
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Abstract

Rett syndrome (RTT) is a severe neurological disorder that is caused by mutations in the MECP2 gene. Many missense mutations causing RTT are clustered in the DNA-binding domain of MeCP2, suggesting that association with chromatin is critical for its function. We identified a second mutational cluster in a previously uncharacterized region of MeCP2. We found that RTT mutations in this region abolished the interaction between MeCP2 and the NCoR/SMRT co-repressor complexes. Mice bearing a common missense RTT mutation in this domain exhibited severe RTT-like phenotypes. Our data are compatible with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 'bridge' between the NCoR/SMRT co-repressors and chromatin.

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  • MeCP2 represses transcription in a gene-specific manner, interacting with the co-repressor complexes mSIN3A and NCoR1/SMRT.

    “Consistently, MeCP2 represses transcription in a gene-specific manner, interacting with the co-repressor complexes mSIN3A and NCoR1/SMRT [70,76].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [70]

    The Results (page unavailable) confirm MeCP2’s interactions with both SIN3A and NCoR/SMRT and show repression of a reporter gene. The Discussion (page unavailable) describes silencing of specific genes as a possibility, alongside global inhibition of transcriptional noise; it does not establish gene-specific repression as a general fact. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The interaction between MeCP2 and the NCoR1/SMRT complex is facilitated by the NCoR1/SMRT interaction domain located at MeCP2 amino acids 285-309.

    “Furthermore, this group found that the interaction between MeCP2 and the NCoR1/SMRT complex was facilitated by the NCoR1/SMRT interaction domain (NID) located at MeCP2 amino acids 285–309 [70,71].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [70]

    The Results identify a MeCP2 NCoR/SMRT interaction domain and report that residues 269–309 were necessary for binding in deletion experiments. They also report direct binding by a peptide spanning residues 285–319. The claimed boundary of 285–309 is not established by either result. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Such MECP2 missense mutations recapitulate Rett Syndrome phenotypes in mice.

    “Such mutations recapitulate Rett Syndrome phenotypes in mice”

    From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [53]

    The Results and Discussion report that mice bearing the MeCP2 R306C missense mutation developed severe Rett-like phenotypes. The paper establishes this for R306C, but the claim’s plural wording extends the finding to MECP2 missense mutations more generally. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • MeCP2 serves as a bridge between methylated DNA and the NCoR1/SMRT co-repressor complex, anchoring the complex to DNA via its NID and MBD.

    “These findings have led to a model wherein MeCP2 serves as a bridge between methylated DNA and the corepressor complex, anchoring the NCoR1/SMRT complex to DNA via its NID and MBD, respectively.”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [70]

  • Five of the seven MeCP2 protein interactors identified were subunits of the NCoR1/SMRT co-repressor complex.

    “Remarkably, five of the seven MeCP2 protein interactors identified were subunits of the NCoR1/SMRT co-repressor complex [70].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [70]

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Cites

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Research works printed but not linked: 35

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Authors
Lyst, M. J., Ekiert, R., Ebert, D. H., Merusi, C., Nowak, J., Selfridge, J., Guy, J., Kastan, N. R., Robinson, N. D., de Lima Alves, F., Rappsilber, J., Greenberg, M. E., & Bird, A.
Affiliations
  • Wellcome Centre for Cell Biology (GB)
  • Harvard University (US)
Corresponding author
Bird, Adrian
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2013-06-16
Volume
16
Issue
7
Pages
898-902
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3434
PMC
PMC3786392
OpenAlex
W2122522583
Cited by
410
References
3
Citations by year
2026: 25 · 2025: 27 · 2024: 33 · 2023: 27 · 2022: 23 · 2021: 38 · 2020: 30 · 2019: 36 · 2018: 35 · 2017: 32 · 2016: 34 · 2015: 26 · 2014: 28 · 2013: 16
FWCI
23.00
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (091020, 084229, 092076, 091580)
  • National Institutes of Health (5r01ns048276-15)
  • National Institute of Mental Health (K08MH090306, K08MH90306)
  • National Institute of Neurological Disorders and Stroke (R01-NS-048276)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
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 › Genetics › Genomics and Rare Diseases
Keywords
Rett syndrome, MeCP2, protein-protein interaction, missense mutations, C-terminal domain, transcriptional repression, knock-in mice, motor phenotype, chromatin, DNA-binding domain
MeSH terms
Histone Deacetylase 3, Animals, Brain, Cells, Cultured, Disease Models, Animal, Exploratory Behavior, Histone Deacetylases, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, Mutation, Rett Syndrome, Immunoprecipitation, Green Fluorescent Proteins, Mice, Methyl-CpG-Binding Protein 2, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2

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