Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Nat Commun. 2017 Mar 20;8:14758. doi: 10.1038/ncomms14758.
Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.
染色质修饰基因的突变常与神经发育疾病相关。本文研究表明，与 CHARGE 综合征密切相关的染色质螺旋酶 DNA 结合蛋白 7（Chd7）对于正常小脑发育是不可或缺的。在小脑颗粒神经元祖细胞中敲除 Chd7 会导致小鼠小脑发育不全，这是由于颗粒神经元分化受损、凋亡诱导以及浦肯野细胞异常定位所致，这与 CHARGE 患者小脑的已知临床特征非常相似。组合分子分析表明，Chd7 对于维持开放染色质以及激活颗粒神经元分化所必需的基因的激活是必需的。我们进一步证明，Chd7 和 Top2b 对于小脑颗粒神经元中一组长神经元基因的转录都是必需的。总之，我们的综合分析揭示了一个机制，即染色质重塑因子通过控制细胞特异性分化的核心转录程序来调节大脑发育。
