Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results have demonstrated that a subset of gene promoters, termed Epromoters, works as bona fide enhancers and regulates distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We found that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Based on these findings, we developed a bioinformatic pipeline to predict Epromoter-like regulated clusters. Using this pipeline, we identified and validated the involvement of Epromoter-containing clusters in the regulation of several inflammatory and stress responses. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of a subset of gene clusters during the inflammatory and stress responses.