Not many people can resist the allure of the ubiquitous neon signs promising fantastic two-for-the-price-of-one offers that promise to double the value of their hard-earned cash. Interestingly, these bargain offers also seem to be a feature in the human genome as a subset of promoters provide extra value by also acting as enhancers for other genes.
Unfortunately, there are no easy-to-read neon signs within the genome that point scientists towards these so-called “Epromoters”. Therefore, researchers and resourceful shoppers from the lab of Salvatore Spicuglia (Aix-Marseille University, France) developed a new high-throughput reporter assay, called CapStarr-seq, which can assess selected promoter regions for enhancer activity in a cell-based test and actively seek out two-for-the-price-of-one offers present in our genome.
Initial assessments by Dao et al. determined enhancer activity of all promoters of RefSeq-defined human coding genes (regions −200 to +50 bp around the transcriptional start site that drive transcription of an adjacent gene) in mouse somatic cell lines. The CapStarr-seq assay indicated that around 2-3% of these active gene promoters also displayed enhancer activity and could be faithfully denominated as Epromoters. Further characterization of Epromoters in human somatic cells demonstrated distinct epigenomic and genomic features, as Epromoters contained histone modifications characteristic of both promoters (H3K4me3) and enhancers (H3K27ac and p300 binding) and located close to both housekeeping and stress response genes.
Finally, detailed analysis confirmed that Epromoters frequently interacted with other gene promoters and the application of CRISPR/Cas9-mediated genomic deletions indicated the involvement of Epromoters in the cis-regulation of distal genes. Together, this suggests that Epromoters do indeed provide a “two-for-the-price-of-one” deal by functioning as bona fide enhancers as well as promoters.
The authors suggest that these findings will profoundly affect our current understanding of gene regulation during normal and disease development and hypothesize that Epromoters may function to ensure the rapid and coordinated expression of a particular subset of genes in response to various cell stressors. Future studies will concentrate on the mechanisms controlling Epromoter-promoter and Epromoter-enhancer interactions as well as the influence of Epromoters on transcription factories.
While the two-for-the-price-of-one offer stops here, be sure to double your pleasure by reading this solitary study from Nature Genetics, June 2017.