Epromoters function as a hub to recruit key transcription factors required for the interferon/inflammatory response

Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Previous results have demonstrated that a subset of gene promoters, also termed Epromoters, works as bona fide enhancers and regulate distal gene expression. We hypothesised that Epromoters might play a key role in the coordination of rapid gene induction in the stress response, in particular during inflammation. Using a high-throughput reporter assay we explored the function of Epromoter in response to type I interferon. We found that STAT1/2 and IRF transcription factors preferentially bind to IFNa-induced Epromoters and distally regulate the activation of interferon-response genes. Similar observations were made in other types of inflammatory response. Our findings suggest that Epromoters might function as a hub to recruit key TFs required for coordinated regulation of gene clusters during the inflammatory response, and more generally upon cellular response to intra- and extra-cellular signals. Genome-wide analysis via ChIP-Seq for H3K27ac, H3k4me3 AND H3k4me1 in K562 cells stimulated with Interferon alpha for 6 hours and non stimulated; and IRF9 in K562 cells stimulated with interferon alpha for 6 hours; and, CapSTARR-seq using our ref-seq promoter library in K562 cells stimulated with IFNa for 6 hours.