Department of Computer Science, University of Miami, Miami, FL, 33146, USA.
Scipher Medicine Inc, Waltham, MA, 02453, USA.
Sci Rep. 2022 Mar 3;12(1):3528. doi: 10.1038/s41598-022-07035-4.
Understanding the mechanisms of tissue-specific transcriptional regulation is crucial as mis-regulation can cause a broad range of diseases. Here, we investigated transcription factors (TF) that are indispensable for the topological control of tissue specific and cell-type specific regulatory networks as a function of their binding to regulatory elements on promoters and enhancers of corresponding target genes. In particular, we found that promoter-binding TFs that were indispensable for regulatory network control regulate genes that are tissue-specifically expressed and overexpressed in corresponding cancer types. In turn, indispensable, enhancer-binding TFs were enriched with disease and signaling genes as they control an increasing number of cell-type specific regulatory networks. Their target genes were cell-type specific for blood and immune-related cell-types and over-expressed in blood-related cancers. Notably, target genes of indispensable enhancer-binding TFs in cell-type specific regulatory networks were enriched with cancer drug targets, while target genes of indispensable promoter-binding TFs were bona-fide targets of cancer drugs in corresponding tissues. Our results emphasize the significant role control analysis of regulatory networks plays in our understanding of transcriptional regulation, demonstrating potential therapeutic implications in tissue-specific drug discovery research.
理解组织特异性转录调控的机制至关重要，因为调控失常可能导致广泛的疾病。在这里，我们研究了转录因子（TF），它们作为其结合到相应靶基因启动子和增强子上的调节元件的功能，对于组织特异性和细胞类型特异性调节网络的拓扑控制是必不可少的。特别是，我们发现对于调节网络控制必不可少的启动子结合 TF 调节组织特异性表达和相应癌症类型中过表达的基因。反过来，必不可少的增强子结合 TF 富含疾病和信号基因，因为它们控制越来越多的细胞类型特异性调节网络。它们的靶基因是血液和免疫相关细胞类型的细胞类型特异性，并且在血液相关癌症中过表达。值得注意的是，细胞类型特异性调节网络中必不可少的增强子结合 TF 的靶基因富含癌症药物靶点，而相应组织中必不可少的启动子结合 TF 的靶基因是癌症药物的真正靶点。我们的结果强调了调控网络控制分析在我们理解转录调控中的重要作用，表明在组织特异性药物发现研究中具有潜在的治疗意义。
