title: Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior.
abstract: Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2R306Cmutation 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 MECP2R306Cneural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2R306Ccells 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.
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alexi
authors.initials: A
authors.lastname: Nott
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jemmie
authors.initials: J
authors.lastname: Cheng
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Gao
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Yuan-Ta
authors.initials: YT
authors.lastname: Lin
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Gjoneska
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Tak
authors.initials: T
authors.lastname: Ko
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|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.).
authors.forename: Paras
authors.initials: P
authors.lastname: Minhas
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alicia Viridiana
authors.initials: AV
authors.lastname: Zamudio
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|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.).
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Feiran
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics; D012919:Social Behavior; D000099186:Histone Deacetylase 3
chemical_list: D051858:Forkhead Transcription Factors; D006655:Histone Deacetylases; D051783:Methyl-CpG-Binding Protein 2; D000099186:Histone Deacetylase 3; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse