Combinatorial interactions among transcription factors (TFs) are critical for integrating diverse intrinsic and extrinsic signals, fine-tuning regulatory output and increasing the robustness and plasticity of regulatory systems. Current knowledge about combinatorial regulation is rather limited due to the lack of suitable experimental technologies and bioinformatics tools. The rapid accumulation of ChIP-Seq data has provided genome-wide occupancy maps for a large number of TFs and chromatin modification marks for identifying enhancers without knowing individual TF binding sites. Integration of the two data types has not been researched extensively, resulting in underused data and missed opportunities. We describe a novel method for discovering frequent combinatorial occupancy patterns by multiple TFs at enhancers. Our method is based on probabilistic item set mining and takes into account uncertainty in both types of ChIP-Seq data. By joint analysis of 108 TFs in four human cell types, we found that cell-type-specific interactions among TFs are abundant and that the majority of enhancers have flexible architecture. We show that several families of transposable elements disproportionally overlap with enhancers with combinatorial patterns, suggesting that these transposable element families play an important role in the evolution of combinatorial regulation.
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