Neves Alexandre, Eisenman Robert N
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
Biol Open. 2019 Apr 4;8(4):bio042168. doi: 10.1242/bio.042168.
The transcriptional mechanisms that allow neural stem cells (NSC) to balance self-renewal with differentiation are not well understood. Employing an RNAi screen we identify here NSC-TAFs, a subset of nine TATA-binding protein associated factors (TAFs), as NSC identity genes in We found that depletion of NSC-TAFs results in decreased NSC clone size, reduced proliferation, defective cell polarity and increased hypersensitivity to cell cycle perturbation, without affecting NSC survival. Integrated gene expression and genomic binding analyses revealed that NSC-TAFs function with both TBP and TRF2, and that NSC-TAF-TBP and NSC-TAF-TRF2 shared target genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identity by promoting cell cycle progression and NSC cell polarity. Because pathogenic variants in a subset of TAFs have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders.
神经干细胞（NSC）如何平衡自我更新与分化的转录机制尚未完全明确。我们通过RNA干扰筛选，鉴定出NSC-TAFs，即9个TATA结合蛋白相关因子（TAFs）中的一个子集，作为NSC的特征基因。我们发现，NSC-TAFs的缺失导致NSC克隆大小减小、增殖减少、细胞极性缺陷以及对细胞周期扰动的超敏反应增加，但不影响NSC的存活。综合基因表达和基因组结合分析表明，NSC-TAFs与TBP和TRF2共同发挥作用，且NSC-TAF-TBP和NSC-TAF-TRF2的共同靶基因编码不同子集的转录因子和RNA结合蛋白，这些蛋白在NSC特征和脑发育中具有既定或新出现的作用。综上所述，我们的结果表明，核心启动子因子通过促进细胞周期进程和NSC细胞极性，对NSC特征具有选择性需求。由于一部分TAFs中的致病变体都与人类神经系统疾病有关，这项工作可能会刺激并为未来TAF相关神经系统疾病的动物模型提供信息。
