The Chromatin Remodeler CHD7 Regulates Adult Neurogenesis via Activation of SoxC Transcription Factors
The Chromatin Remodeler CHD7 Regulates Adult Neurogenesis via Activation of SoxC Transcription Factors
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DOI：
10.1016/j.stem.2013.05.002
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发表时间：
2013-07-03
期刊：
影响因子：
23.9
通讯作者：
Liu, Hai-Kun
中科院分区：
文献类型：
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作者：
Feng, Weijun;Khan, Muhammad Amir;Liu, Hai-Kun
调节中枢神经系统神经发生的染色质因子仍有待探索。在此，我们证明染色质重塑因子染色质解旋酶DNA结合蛋白7（CHD7）——一种在人类CHARGE综合征中经常发生突变的蛋白质，是哺乳动物大脑中神经发生的主要调节因子。CHD7在活跃分裂的神经干细胞（NSCs）和祖细胞中选择性表达。神经干细胞中CHD7的基因失活导致神经元分化减少以及新生神经元树突发育异常。引人注目的是，体育锻炼可以挽救成年海马齿状回中的CHD7突变表型。我们进一步表明，在神经干细胞中，CHD7通过将Sox4和Sox11基因的启动子重塑为开放的染色质状态来刺激它们的表达。我们的研究证明了CHD7在激活神经干细胞的神经元分化程序中的关键作用，从而为干细胞分化的表观遗传调控以及人类CHARGE综合征的分子机制提供了见解。
Chromatin factors that regulate neurogenesis in the central nervous system remain to be explored. Here, we demonstrate that the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7), a protein frequently mutated in human CHARGE syndrome, is a master regulator of neurogenesis in mammalian brain. CHD7 is selectively expressed in actively dividing neural stem cells (NSCs) and progenitors. Genetic inactivation of CHD7 in NSCs leads to a reduction of neuronal differentiation and aberrant dendritic development of newborn neurons. Strikingly, physical exercise can rescue the CHD7 mutant phenotype in the adult hippocampal dentate gyrus. We further show that in NSCs, CHD7 stimulates the expression of Sox4 and Sox11 genes via remodeling their promoters to an open chromatin state. Our study demonstrates an essential role of CHD7 in activation of the neuronal differentiation program in NSCs, thus providing insights into epigenetic regulation of stem cell differentiation and molecular mechanism of human CHARGE syndrome.