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Nat Neurosci. 2016 Nov;19(11):1497-1505. doi: 10.1038/nn.4347. Epub 2016 Jul 18.

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

Nott A1,2, Cheng J1,2, Gao F1,2, Lin YT1,2, Gjoneska E1,2,3, Ko T1,2, Minhas P1,2,4, Zamudio AV1,2, Meng J1,2,4, Zhang F5, Jin P5, Tsai LH1,2,3.

Author information

  • 1The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 3Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 4Present 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.).
  • 5Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

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.

PMID:
27428650
PMCID:
PMC5083138
DOI:
10.1038/nn.4347
[PubMed - in process]
Free PMC Article
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