Understanding Tissue-Specific Gene Regulation

Abstract

Summary: Although all human tissues carry out common processes, tissues are distinguished by gene expression patterns, implying that distinct regulatory programs control tissue specificity. In this study, we investigate gene expression and regulation across 38 tissues profiled in the Genotype-Tissue Expression project. We find that network edges (transcription factor to target gene connections) have higher tissue specificity than network nodes (genes) and that regulating nodes (transcription factors) are less likely to be expressed in a tissue-specific manner as compared to their targets (genes). Gene set enrichment analysis of network targeting also indicates that the regulation of tissue-specific function is largely independent of transcription factor expression. In addition, tissue-specific genes are not highly targeted in their corresponding tissue network. However, they do assume bottleneck positions due to variability in transcription factor targeting and the influence of non-canonical regulatory interactions. These results suggest that tissue specificity is driven by context-dependent regulatory paths, providing transcriptional control of tissue-specific processes. : Understanding gene regulation is important for many fields in biology and medicine. Sonawane et al. reconstruct and investigate regulatory networks for 38 human tissues. They find that regulation of tissue-specific function is largely independent of transcription factor expression and that tissue specificity appears to be mediated by tissue-specific regulatory network paths. Keywords: GTEx, gene regulation, regulatory networks, gene expression, transcriptome, network biology, transcriptional regulation, tissue specificity, transcription factors, network medicine