Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cell Syst. 2019 Aug 28;9(2):167-186.e12. doi: 10.1016/j.cels.2019.05.012. Epub 2019 Jul 10.
Neuroepithelial stem cells (NSC) from different anatomical regions of the embryonic neural tube's rostrocaudal axis can differentiate into diverse central nervous system tissues, but the transcriptional regulatory networks governing these processes are incompletely understood. Here, we measure region-specific NSC gene expression along the rostrocaudal axis in a human pluripotent stem cell model of early central nervous system development over a 72-h time course, spanning the hindbrain to cervical spinal cord. We introduce Escarole, a probabilistic clustering algorithm for non-stationary time series, and combine it with prior-based regulatory network inference to identify genes that are regulated dynamically and predict their upstream regulators. We identify known regulators of patterning and neural development, including the HOX genes, and predict a direct regulatory connection between the transcription factor POU3F2 and target gene STMN2. We demonstrate that POU3F2 is required for expression of STMN2, suggesting that this regulatory connection is important for region specificity of NSCs.
神经上皮干细胞（NSC）来自胚胎神经管的头侧-尾侧轴的不同解剖区域，可以分化为多种中枢神经系统组织，但控制这些过程的转录调控网络尚不完全清楚。在这里，我们在人类多能干细胞模型中测量了早期中枢神经系统发育过程中沿着头侧-尾侧轴的区域特异性 NSC 基因表达，跨越后脑到颈脊髓，历时 72 小时。我们引入了 Escarole，这是一种用于非平稳时间序列的概率聚类算法，并将其与基于先验的调控网络推断相结合，以识别动态调控的基因，并预测其上游调控因子。我们鉴定了已知的模式形成和神经发育调控因子，包括 HOX 基因，并预测转录因子 POU3F2 和靶基因 STMN2 之间存在直接的调控关系。我们证明 POU3F2 是 STMN2 表达所必需的，这表明这种调控关系对 NSC 的区域特异性很重要。
