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Cited by 110Genetics and Neurodevelopmental DisordersFOXO transcription factor regulationGenetic Neurodegenerative Diseases

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

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Nott, Alexi, Cheng, Jemmie, Gao, Fan, Lin, Yuan-Ta, Gjoneska, Elizabeta, Ko, Tak, Minhas, Paras, Zamudio, Alicia Viridiana +4 more·2016·Nature Neuroscience
DOI 10.1038/nn.4347PMC PMC5083138
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Abstract

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2 R306C 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 MECP2 R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2 R306C 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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  • Neuron-specific deletion of Hdac3 produces viable mice that gradually develop a phenotype very similar to that of Mecp2 null mice including abnormal motor coordination, reduced sociability and cognitive defects.

    “While both Ncor1 and Hdac3 null mice die as embryos, a neuron-specific deletion of Hdac3 produces viable mice that gradually develop a phenotype very similar to that of Mecp2 null mice including abnormal motor coordination, reduced sociability and cognitive defects [189].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [189]

    The Results sections on locomotor behavior and social and cognitive deficits report viable forebrain-neuron Hdac3 conditional knockout mice with impaired motor coordination, aberrant sociability, and memory deficits. The Discussion says these behaviors resemble those in Mecp2 loss-of-function models. The paper does not establish that the deficits developed gradually, and its comparison is to Mecp2 loss-of-function models, particularly forebrain-specific knockouts, rather than specifically to Mecp2 null mice. (LLM, conf=0.87)

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Cited by

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Authors
Nott, A., Cheng, J., Gao, F., Lin, Y.-T., Gjoneska, E., Ko, T., Minhas, P., Zamudio, A. V., Meng, J., Zhang, F., Jin, P., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Broad Institute (US)
  • Emory University (US)
Corresponding author
Nott, Alexi
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2016-07-18
Volume
19
Issue
11
Pages
1497-1505
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4347
PMC
PMC5083138
OpenAlex
W2491676496
Cited by
110
References
8
Citations by year
2026: 7 · 2025: 9 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 10 · 2019: 14 · 2018: 15 · 2017: 12 · 2016: 6
FWCI
12.66
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • PMC
Funders
  • National Institute of Mental Health (R01MH076090, R01MH102690)
  • National Institute of General Medical Sciences (T32GM007287)
  • National Institute of Neurological Disorders and Stroke (R01NS079625, R01NS078839, R01NS051630)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
Rett syndrome, MeCP2, HDAC3, FOXO, histone deacetylation, transcriptional regulation, social behavior, cognitive impairment, neuronal gene expression, chromatin profiling, neurodevelopmental disorders
MeSH terms
Histone Deacetylase 3, Animals, Histone Deacetylases, Humans, Mice, Transgenic, Mutation, Neurons, Phenotype, Social Behavior, Rett Syndrome, Methyl-CpG-Binding Protein 2, Forkhead Transcription Factors, Neural Stem Cells

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