School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Sci Rep. 2020 Jul 31;10(1):12960. doi: 10.1038/s41598-020-69791-5.
Concepts from dynamical systems theory, including multi-stability, oscillations, robustness and stochasticity, are critical for understanding gene regulation during cell fate decisions, inflammation and stem cell heterogeneity. However, the prevalence of the structures within gene networks that drive these dynamical behaviours, such as autoregulation or feedback by microRNAs, is unknown. We integrate transcription factor binding site (TFBS) and microRNA target data to generate a gene interaction network across 28 human tissues. This network was analysed for motifs capable of driving dynamical gene expression, including oscillations. Identified autoregulatory motifs involve 56% of transcription factors (TFs) studied. TFs that autoregulate have more interactions with microRNAs than non-autoregulatory genes and 89% of autoregulatory TFs were found in dual feedback motifs with a microRNA. Both autoregulatory and dual feedback motifs were enriched in the network. TFs that autoregulate were highly conserved between tissues. Dual feedback motifs with microRNAs were also conserved between tissues, but less so, and TFs regulate different combinations of microRNAs in a tissue-dependent manner. The study of these motifs highlights ever more genes that have complex regulatory dynamics. These data provide a resource for the identification of TFs which regulate the dynamical properties of human gene expression.
动态系统理论的概念，包括多稳定性、振荡、鲁棒性和随机性，对于理解细胞命运决定、炎症和干细胞异质性过程中的基因调控至关重要。然而，驱动这些动态行为的基因网络结构的普遍性，如转录因子的自身调控或 microRNA 的反馈，尚不清楚。我们整合转录因子结合位点（TFBS）和 microRNA 靶标数据，在 28 个人类组织中生成一个基因相互作用网络。该网络分析了能够驱动动态基因表达的模式，包括振荡。鉴定出的自身调控模式涉及 56%的研究转录因子（TFs）。与非自身调控基因相比，自身调控的 TF 与 microRNA 的相互作用更多，并且 89%的自身调控 TF 存在于与 microRNA 的双重反馈模式中。自身调控和双重反馈模式在网络中均有富集。在组织间，自身调控的 TF 高度保守。与组织间的 microRNAs 存在双重反馈模式，但保守性较低，TF 以组织依赖的方式调节不同的 microRNA 组合。这些模式的研究突出了越来越多具有复杂调控动力学的基因。这些数据为鉴定调节人类基因表达动态特性的 TF 提供了资源。
