Tissue-specific gene expression is generally regulated by more than a single transcription factor (TF). Multiple TFs work in concert to achieve tissue specificity. In order to explore these complex TF interaction networks, we performed a large-scale analysis of TF interactions for 30 human tissues. We first identified tissue-specific genes for 30 tissues based on gene expression databases. We then evaluated the relationships between TFs using the relative position and co-occurrence of their binding sites in the promoters of tissue-specific genes. The predicted TF-TF interactions were validated by both known protein-protein interactions and co-expression of their target genes. We found that our predictions are enriched in known protein-protein interactions (>80 times that of random expectation). In addition, we found that the target genes show the highest co-expression in the tissue of interest. Our findings demonstrate that non-tissue specific TFs play a large role in regulation of tissue-specific genes. Furthermore, they show that individual TFs can contribute to tissue specificity in different tissues by interacting with distinct TF partners. Lastly, we identified several tissue-specific TF clusters that may play important roles in tissue-specific gene regulation.
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