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Abstract
Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt (Tau) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.
Original language | English |
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Pages (from-to) | 1514-1524 |
Number of pages | 11 |
Journal | Genes & Development |
Volume | 32 |
Issue number | 23-24 |
Early online date | 21 Nov 2018 |
DOIs | |
Publication status | Published - 1 Dec 2018 |
Keywords / Materials (for Non-textual outputs)
- histone deacetylase 3
- MeCP2
- NCoR
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Dive into the research topics of 'Toxicity of overexpressed MeCP2 is independent of HDAC3 activity'. Together they form a unique fingerprint.Projects
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Profiles
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Adrian Bird
- School of Biological Sciences - Buchanan Chair of Genetics
- Edinburgh Neuroscience
- Centre for Engineering Biology
Person: Academic: Research Active