Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Nature Publishing Group
2017
|
| Online Access: | http://hdl.handle.net/1721.1/112683 https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0003-4000-8827 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0002-3255-4740 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1811077421384859648 |
|---|---|
| author | Zhang, Feiran Jin, Peng Nott, Alexander Cheng, Jemmie Gao, Fan Lin, Yuan-Ta Gjoneska, Elizabeta Ko, Tak Minhas, Paras S Zamudio Montes de Oca, Alicia Meng, Jia Tsai, Li-Huei |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Zhang, Feiran Jin, Peng Nott, Alexander Cheng, Jemmie Gao, Fan Lin, Yuan-Ta Gjoneska, Elizabeta Ko, Tak Minhas, Paras S Zamudio Montes de Oca, Alicia Meng, Jia Tsai, Li-Huei |
| author_sort | Zhang, Feiran |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:42:45Z |
| format | Article |
| id | mit-1721.1/112683 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:42:45Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1126832022-09-30T22:27:55Z Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior Zhang, Feiran Jin, Peng Nott, Alexander Cheng, Jemmie Gao, Fan Lin, Yuan-Ta Gjoneska, Elizabeta Ko, Tak Minhas, Paras S Zamudio Montes de Oca, Alicia Meng, Jia Tsai, Li-Huei Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Nott, Alexander Cheng, Jemmie Gao, Fan Lin, Yuan-Ta Gjoneska, Elizabeta Ko, Tak Minhas, Paras S Zamudio Montes de Oca, Alicia Meng, Jia Tsai, Li-Huei 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. National Institutes of Health (U.S.) (Grant NS78839) 2017-12-11T15:39:19Z 2017-12-11T15:39:19Z 2016-07 2016-04 2017-12-11T13:47:08Z Article http://purl.org/eprint/type/JournalArticle 1097-6256 1546-1726 http://hdl.handle.net/1721.1/112683 Nott, Alexi et al. “Histone Deacetylase 3 Associates with MeCP2 to Regulate FOXO and Social Behavior.” Nature Neuroscience 19, 11 (July 2016): 1497–1505 © Nature America, Inc, part of Springer Nature https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0003-4000-8827 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0002-3255-4740 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0003-1262-0592 http://dx.doi.org/10.1038/NN.4347 Nature Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Zhang, Feiran Jin, Peng Nott, Alexander Cheng, Jemmie Gao, Fan Lin, Yuan-Ta Gjoneska, Elizabeta Ko, Tak Minhas, Paras S Zamudio Montes de Oca, Alicia Meng, Jia Tsai, Li-Huei Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title | Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title_full | Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title_fullStr | Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title_full_unstemmed | Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title_short | Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior |
| title_sort | histone deacetylase 3 associates with mecp2 to regulate foxo and social behavior |
| url | http://hdl.handle.net/1721.1/112683 https://orcid.org/0000-0002-2029-7193 https://orcid.org/0000-0003-4000-8827 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0002-3255-4740 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0003-1262-0592 |
| work_keys_str_mv | AT zhangfeiran histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT jinpeng histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT nottalexander histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT chengjemmie histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT gaofan histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT linyuanta histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT gjoneskaelizabeta histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT kotak histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT minhasparass histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT zamudiomontesdeocaalicia histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT mengjia histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior AT tsailihuei histonedeacetylase3associateswithmecp2toregulatefoxoandsocialbehavior |