A time course experiment is a widely used design in the study of cellular processes such as differentiation or response to stimuli. In this paper, we propose time course regulatory analysis (TimeReg) as a method for the analysis of gene regulatory networks based on paired gene expression and chromatin accessibility data from a time course. TimeReg can be used to prioritize regulatory elements, to extract core regulatory modules at each time point, to identify key regulators driving changes of the cellular state, and to causally connect the modules across different time points. We applied the method to analyze paired chromatin accessibility and gene expression data from a retinoic acid (RA)-induced mouse embryonic stem cells (mESCs) differentiation experiment. The analysis identified 57,048 novel regulatory elements regulating cerebellar development, synapse assembly, and hindbrain morphogenesis, which substantially extended our knowledge of cis-regulatory elements during differentiation. Using single-cell RNA-seq data, we showed that the core regulatory modules can reflect the properties of different subpopulations of cells. Finally, the driver regulators are shown to be important in clarifying the relations between modules across adjacent time points. As a second example, our method on Ascl1-induced direct reprogramming from fibroblast to neuron time course data identified Id1/2 as driver regulators of early stage of reprogramming.

中文翻译：

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基于配对表达和染色质可及性数据的时程调控分析。


时程实验是细胞过程研究中广泛使用的设计，例如分化或对刺激的反应。在本文中，我们提出时间过程调控分析（TimeReg）作为一种基于时间过程中配对基因表达和染色质可及性数据的基因调控网络分析方法。 TimeReg 可用于对调节元件进行优先级排序，提取每个时间点的核心调节模块，识别驱动细胞状态变化的关键调节因子，并将不同时间点的模块进行因果连接。我们应用该方法分析了视黄酸 (RA) 诱导的小鼠胚胎干细胞 (mESC) 分化实验中的配对染色质可及性和基因表达数据。该分析确定了 57,048 个调节小脑发育、突触组装和后脑形态发生的新调控元件，这大大扩展了我们对分化过程中顺式调控元件的了解。利用单细胞RNA-seq数据，我们证明核心调控模块可以反映不同细胞亚群的特性。最后，驱动调节器对于阐明相邻时间点模块之间的关系非常重要。作为第二个例子，我们对 Ascl1 诱导的从成纤维细胞到神经元的直接重编程时程数据的方法将 Id1/2 确定为重编程早期阶段的驱动调节因子。