Abstract
Approximately 2%–3% of gene promoters also display distal enhancer activity (termed Epromoters).
Major finding: Approximately 2%–3% of gene promoters also display distal enhancer activity (termed Epromoters).
Concept: Epromoters were associated with genes regulating basic processes and cellular stress responses.
Impact: Epromoters reveal complex gene regulatory mechanisms that may be relevant in cancer or other diseases.
Gene expression is regulated by both transcription start site (TSS)–proximal promoters and gene-distal enhancers. However, there are broad similarities between promoters and enhancers, and promoters with enhancer activity have been reported. TSS-overlapping enhancers have been identified, but the role of these elements in the regulation of distal gene expression has not been fully elucidated. Dao, Galindo-Albarrán, and colleagues used CapStarr-seq, a high-throughput enhancer reporter assay, to characterize promoters that display enhancer activity. TSS-proximal enhancers were observed in mouse cell lines, and displayed less tissue-specificity than distal enhancers. These proximal enhancers were enriched from −300 bp to +100 bp, overlapping with core promoter regions near the TSS. CapStarr-seq also identified TSS-overlapping enhancers (termed Epromoters) in human cells, with 2%–3% of promoters characterized as Epromoters. These Epromoters had similar levels of H3K4me3 as typical promoters, but had an enhanced H3K27ac3/H3K4me3 ratio in the cell types where they were active. Gene ontology analysis revealed that Epromoters were associated with genes involved in basic processes and cellular stress response. Further, Epromoters were associated with higher gene expression than typical promoters, but their enhancer activity was not associated with increased expression of genes compared with typical enhancers, suggesting that the promoter and enhancer functions of Epromoters may be separate. However, CRISPR/Cas9-mediated disruption of Epromoters demonstrated that they regulate expression of distal genes, validating their function as enhancers. Epromoters were associated with rapid activation of distal interferon response genes, allowing a rapid response to external stress stimuli. Furthermore, human genetic variation within Epromoters was associated with a strong effect on distal gene expression. The characterization of Epromoters with dual promoter and enhancer activities provides further insight into mechanisms of transcriptional regulation, which may be relevant in cancer and other diseases.
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