Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR

Daniel 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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)341-345
Number of pages5
JournalNature
Volume499
Issue number7458
DOIs
StatePublished - 2013
Externally publishedYes

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Methyl-CpG-Binding Protein 2
Co-Repressor Proteins
Threonine
Rett Syndrome
Phosphorylation
Mutation
Aptitude
Cytosine
Brain-Derived Neurotrophic Factor
Missense Mutation
Regulator Genes
Autistic Disorder
Nuclear Proteins
Epigenomics
Cyclic AMP
Histones

ASJC Scopus subject areas

  • General

Cite this

Ebert, D., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., ... Greenberg, M. E. (2013). Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature, 499(7458), 341-345. https://doi.org/10.1038/nature12348

Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. / Ebert, Daniel; Gabel, Harrison W.; Robinson, Nathaniel D.; Kastan, Nathaniel R.; Hu, Linda S.; Cohen, Sonia; Navarro, Adrija J.; Lyst, Matthew J.; Ekiert, Robert; Bird, Adrian P.; Greenberg, Michael E.

In: Nature, Vol. 499, No. 7458, 2013, p. 341-345.

Research output: Contribution to journalArticle

Ebert, D, Gabel, HW, Robinson, ND, Kastan, NR, Hu, LS, Cohen, S, Navarro, AJ, Lyst, MJ, Ekiert, R, Bird, AP & Greenberg, ME 2013, 'Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR', Nature, vol. 499, no. 7458, pp. 341-345. https://doi.org/10.1038/nature12348
Ebert, Daniel ; Gabel, Harrison W. ; Robinson, Nathaniel D. ; Kastan, Nathaniel R. ; Hu, Linda S. ; Cohen, Sonia ; Navarro, Adrija J. ; Lyst, Matthew J. ; Ekiert, Robert ; Bird, Adrian P. ; Greenberg, Michael E. / Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. In: Nature. 2013 ; Vol. 499, No. 7458. pp. 341-345.
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abstract = "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.",
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AU - Hu, Linda S.

AU - Cohen, Sonia

AU - Navarro, Adrija J.

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AB - 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.

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