Activity-Dependent Phosphorylation of MeCP2 T308 Regulates Interaction with NCoR

Daniel Ebert, Matthew Lyst, Robert Ekiert, Adrian Bird, Michael Greenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism that is a leading cause of cognitive dysfunction in females. RTT is caused by mutations in 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 genome1-3. By phosphotryptic mapping, we identify three sites (S86, S274, and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these 2 sites is differentially induced by neuronal activity, brain-derived neurotrophic factor
(BDNF), or agents that elevate the intracellular level of cAMP, suggesting that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. We show here that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the NCoR co-repressor complex and suppresses MeCP2’s ability 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 suggest 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.
Original languageEnglish
Pages (from-to)341–345
JournalNature
Volume499
Issue number7458
DOIs
Publication statusPublished - 16 Jun 2013

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