Document Detail


Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.
MedLine Citation:
PMID:  23770587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that, in neurons, regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome. By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3',5'-cyclic AMP (cAMP), indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MeCP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex.
Authors:
Daniel H Ebert; Harrison W Gabel; Nathaniel D Robinson; Nathaniel R Kastan; Linda S Hu; Sonia Cohen; Adrija J Navarro; Matthew J Lyst; Robert Ekiert; Adrian P Bird; Michael E Greenberg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature     Volume:  499     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-22     Completed Date:  2013-07-30     Revised Date:  2014-08-21    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  341-5     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Co-Repressor Proteins / metabolism*
Humans
Methyl-CpG-Binding Protein 2 / chemistry,  genetics,  metabolism*
Mice
Mutation
Neurons / metabolism
Phosphorylation
Rett Syndrome / genetics
Threonine / metabolism*
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
092076//Wellcome Trust; K08 MH090306/MH/NIMH NIH HHS; K08MH90306/MH/NIMH NIH HHS; P30 HD018655/HD/NICHD NIH HHS; P30-HD 18655/HD/NICHD NIH HHS; R01 NS048276/NS/NINDS NIH HHS; R01NS048276/NS/NINDS NIH HHS; T32 GM007753/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Co-Repressor Proteins; 0/MECP2 protein, human; 0/Methyl-CpG-Binding Protein 2; 2ZD004190S/Threonine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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