Abstract
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.
Highlights
Understanding the mechanisms of tissue-specific transcriptional regulation is crucial as mis-regulation can cause a broad range of diseases
We surmised that the disruption of regulation by such control transcription factors (TF) might result in diseases associated with the underlying tissue, suggesting that their target genes support the transition from disease to healthy states, pointing to potential drug targets
Considering drug targets of 74 approved drugs for 18 different cancer types from the National Cancer Institute (NCI) through D GIdb[18], we found that, except for Brain Tumor and Urothelial Cancer, the targets of all the drugs that treat a particular cancer were enriched in target genes of indispensable promoter-binding TFs in the corresponding tissues (Fig. 2D)
Summary
Understanding the mechanisms of tissue-specific transcriptional regulation is crucial as mis-regulation can cause a broad range of diseases. 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. To understand the roles played by different TFs through their regulatory elements in maintaining the cell state, we determined the TFs that exert topological control over the tissue and cell-type specific networks through binding promoters and enhancers. In our analysis of tissue- and cell-type specific regulatory networks between TFs and target genes, we determined TFs that were indispensable for the topological control of the underlying network as a function of their binding of promoter and enhancers of corresponding target genes. We found that promoterbinding TFs are mostly indispensable for the control of underlying tissue-specific regulatory networks, while
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