Department of Statistics, Stanford University, Stanford, California 94305, USA.
CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100080, China.
Genome Res. 2020 Apr;30(4):622-634. doi: 10.1101/gr.257063.119. Epub 2020 Mar 18.
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 course ulatory 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 -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 -induced direct reprogramming from fibroblast to neuron time course data identified as driver regulators of early stage of reprogramming.
时程实验是研究细胞过程（如分化或对刺激的反应）的常用设计。在本文中，我们提出了基于时程的基因表达和染色质可及性数据对基因调控网络进行分析的时程分析（TimeReg）方法。TimeReg 可用于优先考虑调控元件，提取每个时间点的核心调控模块，识别驱动细胞状态变化的关键调控因子，并在不同时间点之间因果连接模块。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。分析确定了 57048 个新的调控元件，这些调控元件调控小脑发育、突触组装和后脑形态发生，大大扩展了我们在分化过程中对调控元件的认识。使用单细胞 RNA-seq 数据，我们表明核心调控模块可以反映不同细胞亚群的特性。最后，驱动因子的调控因子表明在澄清相邻时间点之间模块之间的关系方面很重要。作为第二个例子，我们对成纤维细胞向神经元时程数据的诱导直接重编程的方法确定了早期重编程的驱动因子的调控因子。
