整合多组学数据揭示胚胎干细胞特异的转录调控与染色质状态交联模式

Understanding the molecular mechanisms for maintaining the self-renewal and pluripotency of embryonic stem cells (ESCs) is the key to developing stem cell therapies. A large number of studies have shown that complex regulatory network and chromatin state characterized by epigenetic modifications play important roles in maintaining the self-renewal and pluripotency of ESC. However, how ESC-specific regulatory network and chromatin state cooperatively function to control ESC is still unknown. In this work, we integrate and analyze multi-omics data derived from next-generation sequencing technology, such as epigenome data (including histone methylation and acetylation, DNA methylation), and transcriptome data. From the perspective of systems biology, ESC-specific transcriptionally active regulators (including TFs and miRNAs) and chromatin states are systematically identified through the fusion of a variety of biological resources and the application of different optimization strategies. By integrating TF-gene, TF-miRNA and miRNA-gene regulatory relationships and mapping ESC-specific chromatin states, a TF-miRNA-gene regulatory network driven by chromatin states is constructed. Subsequently, network motifs each of which contains a TF and a miRNA, both are specifically activated in ESC, are determined. Finally, dissecting and analyzing the cross-talk between regulatory motifs and chromatin states are performed. Our results can help to elucidate how chromatin state cooperates with transcriptional regulation in ESC and reveal the potential molecular mechanisms for maintaining ESC self-renewal and pluripotency.

理解维持胚胎干细胞（ESC）自我更新及其多潜能性的分子机制成为干细胞治疗的关键。大量研究表明复杂调控网络与表观修饰所刻画的基因染色质状态在维持ESC自我更新及其多潜能性中发挥重要的作用。然而，对ESC特异的调控网络与其染色质状态的协同互作所知甚少。本课题集成与分析新一代测序技术产生的多组学数据，如表观基因组数据（包括组蛋白甲基化、乙酰化、DNA甲基化等）、转录组数据，从系统生物学的角度，基于融合生物学资源与优化策略，系统地识别ESC特异激活的TF和miRNA及其基因的染色质状态。整合TF-gene、TF-miRNA、miRNA-gene与染色质状态构建ESC条件下染色质状态驱动的TF-miRNA-gene复杂调控网络，识别ESC特异激活的TF和miRNA为核心的调控模体，分析调控模体与染色质状态的交联模式，阐明染色质状态如何参与转录调控，揭示维持ESC不断自我更新和多潜能性的分子机制。

理解维持胚胎干细胞(ESC)自我更新及其多潜能性的分子机制成为干细胞治疗的关键。大量研究表明复杂调控网络与表观修饰所刻画的基因染色质状态在维持 ESC 自我更新及其多潜能性中发挥重要 的作用。然而,对 ESC 特异的调控网络与其染色质状态的协同互作所知甚少。本课题集成与分析新一 代测序技术产生的多组学数据,如表观基因组数据(包括组蛋白甲基化、乙酰化、DNA 甲基化等)、 转录组数据,从系统生物学的角度,基于融合生物学资源与优化策略,系统地识别 ESC 特异激活的 TF 和 miRNA 及其基因的染色质状态。整合 TF-gene、TF-miRNA、miRNA-gene 与染色质状态构建 ESC 条件 下染色质状态驱动的 TF-miRNA-gene 复杂调控网络,识别 ESC 特异激活的 TF 和 miRNA 为核心的调控 模体,分析调控模体与染色质状态的交联模式,阐明染色质状态如何参与转录调控,揭示维持 ESC 不 断自我更新和多潜能性的分子机制。