Epromoters bind key stress-related transcription factors to regulate clusters of stress response genes.

Cellular and environmental stress triggers the rapid and global reprogramming of gene transcription by coordinated recruitment of a limited number of key inducible transcription factors to cis-regulatory elements. Here, we performed a comprehensive analysis of different stress models and observed that co-induced genes are generally located in close genomic proximity. By integrating gene expression and transcription factor binding resources across different stress models, we identify an enrichment for clusters in which only one of the clusters' promoters recruits the key transcription factors, reminiscent of Epromoters-a type of cis-regulatory element that displays both promoter and enhancer function. Epromoter-regulated clusters were frequently found regardless of the stress or inflammatory response. Predicted Epromoters displayed enhancer activity and regulated clusters of stress-response genes independently of their genomic location. These findings imply that Epromoters are central regulatory elements that control gene clusters in response to acute perturbations.