Wang Junwen, Zhu Xintong, Dai Limeng, Wang Ziyi, Guan Xingying, Tan Xiaoyin, Li Jia, Zhang Mao, Bai Yun, Guo Hong
Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China.
Hum Mol Genet. 2023 Feb 19;32(5):860-872. doi: 10.1093/hmg/ddac240.
Chromatin regulators constitute a fundamental means of transcription regulation, which have been implicated in neurodevelopment and neurodevelopment disorders (NDDs). Supt16, one of candidate genes for NDDs, encodes the large subunit of facilitates chromatin transcription. However, the underlying mechanisms remain poorly understood. Here, Supt16+/- mice was generated, modeling the neurodevelopment disorder. Abnormal cognitive and social behavior was observed in the Supt16 +/- mice. Simultaneously, the number of neurocytes in the cerebral cortex and hippocampus is decreased, which might be resulted from the impairment of mouse neural stem cells (mNSCs) in the SVZ. Supt16 haploinsufficiency affects the proliferation and apoptosis of mNSCs. As the RNA-seq and chromatic immunoprecipitation sequencing assays showed, Supt16 haploinsufficiency disrupts the stemness of mNSCs by inhibiting MAPK signal pathway. Thus, this study demonstrates a critical role of Supt16 gene in the proliferation and apoptosis of mNSCs and provides a novel insight in the pathogenesis of NDDs.
染色质调节因子是转录调控的一种基本方式，与神经发育及神经发育障碍（NDDs）有关。Supt16是NDDs的候选基因之一，编码促进染色质转录的大亚基。然而，其潜在机制仍知之甚少。在此，构建了Supt16+/-小鼠，以模拟神经发育障碍。在Supt16+/-小鼠中观察到异常的认知和社交行为。同时，大脑皮层和海马体中的神经细胞数量减少，这可能是由于脑室下区的小鼠神经干细胞（mNSCs）受损所致。Supt16单倍体不足影响mNSCs的增殖和凋亡。正如RNA测序和染色质免疫沉淀测序分析所示，Supt16单倍体不足通过抑制MAPK信号通路破坏mNSCs的干性。因此，本研究证明了Supt16基因在mNSCs增殖和凋亡中的关键作用，并为NDDs的发病机制提供了新的见解。
