There are an increasing number of reports that characterize the temporal behavior of gene expression at the single-cell level during cell differentiation. Despite accumulation of data describing the heterogeneity of biological responses, the dynamics of gene expression heterogeneity and its regulation during the differentiation process have not been studied systematically. To understand transcriptional heterogeneity during astrocyte differentiation, we analyzed single-cell transcriptional data from cells representing the different stages of astrocyte differentiation. When we compared the transcriptional variability of co-expressed genes between the undifferentiated and differentiated states, we found that there was significant increase in transcriptional variability in the undifferentiated state. The genes showing large changes in both "variability" and "correlation" between neural stem cells (NSCs) and astrocytes were found to be functionally involved in astrocyte differentiation. We determined that these genes are potentially regulated by Ascl1, a previously known oscillatory gene in NSCs. Pharmacological blockade of Ntsr2, which is transcriptionally co-regulated with Ascl1, showed that Ntsr2 may play an important role in the differentiation from NSCs to astrocytes. This study shows the importance of characterizing transcriptional heterogeneity and rearrangement of the co-regulation network between different cell states. It also highlights the potential for identifying novel regulators of cell differentiation that will further increase our understanding of the molecular mechanisms underlying the differentiation process.

中文翻译：

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通过检测星形胶质细胞分化过程中转录异质性和共同调节的动态来鉴定早期细胞命运调节剂。

越来越多的报告描述了细胞分化过程中单细胞水平上基因表达的时间行为。尽管描述生物反应异质性的数据不断积累，但基因表达异质性的动态及其在分化过程中的调控尚未得到系统研究。为了了解星形胶质细胞分化过程中的转录异质性，我们分析了代表星形胶质细胞分化不同阶段的细胞的单细胞转录数据。当我们比较未分化状态和分化状态之间共表达基因的转录变异性时，我们发现未分化状态下转录变异性显着增加。发现神经干细胞（NSC）和星形胶质细胞之间的“变异性”和“相关性”发生巨大变化的基因在功能上参与星形胶质细胞的分化。我们确定这些基因可能受到 Ascl1（一种先前已知的 NSC 振荡基因）的调节。Ntsr2 与 Ascl1 在转录上共同调节，对 Ntsr2 的药理学阻断表明 Ntsr2 可能在 NSC 向星形胶质细胞的分化中发挥重要作用。这项研究表明了表征不同细胞状态之间的转录异质性和共调控网络重排的重要性。它还强调了识别细胞分化的新型调节剂的潜力，这将进一步增加我们对分化过程背后的分子机制的理解。