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Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Nature Neuroscience volume 19, pages 14971505 (2016) | Download Citation

Abstract

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.

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Acknowledgements

We thank E.N. Olson (UT Southwestern Medical Center) for kindly providing the HDAC3f/f mice. We thank M. Sur and A. Banerjee (both at Massachusetts Institute of Technology for providing Mecp2 KO mice. We thank G.-L. Ming (Johns Hopkins University) for kindly providing the C1 iPSC cell line. We thank R. Madabhushi, A. Watson and J. Penney for comments on the manuscript. We thank E. Demmons for help with mouse colony maintenance. This work was supported by US National Institutes of Health grants (MH102690 and NS079625) and Rettsyndrome.org to P.J., and NIH grant NS78839 and the JPB Foundation to L.-H.T.

Author information

Author notes

    • Paras Minhas
    •  & Jia Meng

    Present addresses: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA (P.M.), and Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China (J.M.).

Affiliations

  1. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Alexi Nott
    • , Jemmie Cheng
    • , Fan Gao
    • , Yuan-Ta Lin
    • , Elizabeta Gjoneska
    • , Tak Ko
    • , Paras Minhas
    • , Alicia Viridiana Zamudio
    • , Jia Meng
    •  & Li-Huei Tsai
  2. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Alexi Nott
    • , Jemmie Cheng
    • , Fan Gao
    • , Yuan-Ta Lin
    • , Elizabeta Gjoneska
    • , Tak Ko
    • , Paras Minhas
    • , Alicia Viridiana Zamudio
    • , Jia Meng
    •  & Li-Huei Tsai
  3. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Elizabeta Gjoneska
    •  & Li-Huei Tsai
  4. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Feiran Zhang
    •  & Peng Jin

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Contributions

A.N. and L.-H.T. designed the study, and L.-H.T. directed and coordinated the study. A.N. initiated, planned and performed experimental work. J.C. helped with ChIP experiments. F.G. and J.M. contributed to bioinformatic analysis. P.M. helped with some behavioral experiments. A.V.Z. helped with validation of the RNA-seq. E.G. prepared sequencing libraries for the ChIP-seq experiment. T.K. derived the NPC lines. T.K. and Y.-T.L. helped to maintain the iPSCs. F.Z. and P.J. provided Mecp2 KO tissue. A.N. and L.-H.T. wrote the manuscript with critical input from all of the authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alexi Nott.

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DOI

https://doi.org/10.1038/nn.4347

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