Recurrent enhancer-promoter interactions across samples

Enhancer-promoter interactions (EPIs) are fundamental to gene regulation, and clarifying their recurrence across diverse biological contexts is key to understanding chromatin architecture. Here, we systematically evaluate EPI recurrence using 95 HiChIP and 266 Hi-C datasets spanning multiple cell types, cell lines, and experimental conditions. We find that each of the majority of EPIs identified in any given sample is also observed in other samples, largely independent of assay type, cellular context, or enhancer annotation strategy. EPIs unique to an individual sample tend to occur in regions with fewer neighboring EPIs or in a sample with greater sequencing depth, indicating that many such “unique” EPIs likely reflect low sequencing depth rather than true biological specificity. Collectively, our results suggest that most human EPIs may have already been cataloged, and that gene regulation primarily relies on the selective reuse of a shared pool of EPIs across contexts. Thus, while EPIs are context-specific in pairwise sample comparisons, they are broadly recurrent when considered across a large compendium of samples. These findings underscore the pervasive and reusable nature of EPIs and have important implications for the interpretation of chromatin conformation data.