Synergistic Transcriptional and Post-Transcriptional Regulation of ESC Characteristics by Core Pluripotency Transcription Factors in Protein-Protein Interaction Networks

The molecular mechanism that maintains the pluripotency of embryonic stem cells (ESCs) is not well understood but may be reflected in complex biological networks. However, there have been few studies on the effects of transcriptional and post-transcriptional regulation during the development of ESCs from the perspective of computational systems biology. In this study, we analyzed the topological properties of the “core” pluripotency transcription factors (TFs) OCT4, SOX2 and NANOG in protein-protein interaction networks (PPINs). Further, we identified synergistic interactions between these TFs and microRNAs (miRNAs) in PPINs during ESC development. Results show that there were significant differences in centrality characters between TF-targets and non-TF-targets in PPINs. We also found that there was consistent regulation of multiple “core” pluripotency TFs. Based on the analysis of shortest path length, we found that the module properties were not only within the targets regulated by common or multiple “core” pluripotency TFs but also between the groups of targets regulated by different TFs. Finally, we identified synergistic regulation of these TFs and miRNAs. In summary, the synergistic effects of “core” pluripotency TFs and miRNAs were analyzed using computational methods in both human and mouse PPINs.

维持胚胎干细胞（embryonic stem cells, ESCs）多能性的分子机制尚未得到充分阐明，其相关调控逻辑可通过复杂的生物网络得以体现。然而，从计算系统生物学视角出发，探究转录与转录后调控在胚胎干细胞发育过程中作用的相关研究仍较为匮乏。本研究针对蛋白质相互作用网络（protein-protein interaction networks, PPINs）中核心多能性转录因子（transcription factors, TFs）OCT4、SOX2及NANOG的拓扑特性展开分析。进一步，我们鉴定了胚胎干细胞发育进程中，上述转录因子与微小RNA（microRNAs, miRNAs）在蛋白质相互作用网络内的协同相互作用。研究结果显示，蛋白质相互作用网络中转录因子靶标与非转录因子靶标的中心性特征存在显著差异。同时，我们发现多个核心多能性转录因子存在协同调控现象。通过对最短路径长度的分析，我们发现模块特性不仅存在于由共同或多个核心多能性转录因子调控的靶标内部，也存在于不同转录因子所调控的靶标组之间。最终，我们鉴定得到上述转录因子与微小RNA的协同调控关系。综上，本研究通过计算方法，分别在人类与小鼠的蛋白质相互作用网络中分析了核心多能性转录因子与微小RNA的协同效应。