SummaryAlthough 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.

Highlights d Sex differences are evident in sample-specific gene regulatory networks d TF sex-biased targeting of genes is independent of their differential expression d Sex-biased target genes are enriched for tissue-related functions and diseases d Rich public resource that includes 8,279 gene regulatory networks of 29 tissues

Network medicine is an emerging area of research dealing with molecular and genetic interactions, network biomarkers of disease, and therapeutic target discovery. Large-scale biomedical data generation offers a unique opportunity to assess the effect and impact of cellular heterogeneity and environmental perturbations on the observed phenotype. Marrying the two, network medicine with biomedical data provides a framework to build meaningful models and extract impactful results at a network level. In this review, we survey existing network types and biomedical data sources. More importantly, we delve into ways in which the network medicine approach, aided by phenotype-specific biomedical data, can be gainfully applied. We provide three paradigms, mainly dealing with three major biological network archetypes: protein-protein interaction, expression-based, and gene regulatory networks. For each of these paradigms, we discuss a broad overview of philosophies under which various network methods work. We also provide a few examples in each paradigm as a test case of its successful application. Finally, we delineate several opportunities and challenges in the field of network medicine. We hope this review provides a lexicon for researchers from biological sciences and network theory to come on the same page to work on research areas that require interdisciplinary expertise. Taken together, the understanding gained from combining biomedical data with networks can be useful for characterizing disease etiologies and identifying therapeutic targets, which, in turn, will lead to better preventive medicine with translational impact on personalized healthcare.