Nott Alexi, Cheng Jemmie, Gao Fan, Lin Yuan-Ta, Gjoneska Elizabeta, Ko Tak, Minhas Paras, Zamudio Alicia Viridiana, Meng Jia, Zhang Feiran, Jin Peng, Tsai Li-Huei
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.
Nat Neurosci. 2016 Nov;19(11):1497-1505. doi: 10.1038/nn.4347. Epub 2016 Jul 18.
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2 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 neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2 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.
MECP2基因的突变会导致神经发育障碍雷特综合征（RTT）。RTT错义MECP2突变会阻止MeCP2与NCoR/组蛋白去乙酰化酶3（HDAC3）复合物相互作用；然而，HDAC3在神经元中的功能尚未完全明确。我们发现，小鼠神经元中Hdac3的缺失会引发异常的运动协调、社交能力和认知能力。转录和染色质分析表明，HDAC3正向调控一部分基因，并通过MeCP2被招募到活跃基因的启动子区域。与HDAC3相关的启动子富含FOXO转录因子，并且在Hdac3基因敲除（KO）和Mecp2 KO神经元中FOXO乙酰化水平升高。源自人类RTT患者的MECP2神经祖细胞在HDAC3和FOXO招募以及基因表达方面存在缺陷。对MECP2细胞进行基因编辑以产生同基因对照，挽救了HDAC3-FOXO介导的基因表达损伤。我们的数据表明，HDAC3与MeCP2的相互作用通过FOXO去乙酰化正向调控一部分神经元基因，并且HDAC3的破坏会导致认知和社交障碍。
