Genome-wide characterization of mammalian promoters with distal enhancer functions

Salvatore Spicuglia and colleagues use a high-throughput reporter assay to identify a set of mammalian promoters, termed Epromoters, that display enhancer activity and have distinct genomic and epigenomic features. Through CRISPR–Cas9 gene editing experiments, they show that Epromoters are involved in long-range gene regulation in cis . Gene expression in mammals is precisely regulated by the combination of promoters and gene-distal regulatory regions, known as enhancers. Several studies have suggested that some promoters might have enhancer functions. However, the extent of this type of promoters and whether they actually function to regulate the expression of distal genes have remained elusive. Here, by exploiting a high-throughput enhancer reporter assay, we unravel a set of mammalian promoters displaying enhancer activity. These promoters have distinct genomic and epigenomic features and frequently interact with other gene promoters. Extensive CRISPR–Cas9 genomic manipulation demonstrated the involvement of these promoters in the cis regulation of expression of distal genes in their natural loci. Our results have important implications for the understanding of complex gene regulation in normal development and disease.