Séminaire de Salvatore SPICUGLIA, PhD - Marseille

Assessment of enhancer activity by high-throughput reporter assays: Identification of core promoters with distal enhancer functions

ABSTRACT

Gene expression in mammals is precisely regulated by combination of promoters and gene-distal regulatory regions, known as enhancers. Recent studies have shown broad similarities between enhancers and promoters and suggested that some promoters might also play 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 CapStarr-seq, a high-throughput enhancer reporter assay, we unravel a substantial proportion of mammalian promoters displaying enhancer activity, named hereafter Epromoters. Compared to classical promoters and distal enhancers, Epromoters display distinct genomic and epigenomic features and are associated with stress response. By using comprehensive CRISPR/Cas9 genomic deletions we demonstrated that Epromoters are frequently involved in cis-regulation of distal gene expression in their endogenous context, therefore functioning as bona fide enhancers. Furthermore, human genetic variations within Epromoters were associated with a strong effect on distal gene expression. Our results highlight a new category of regulatory elements playing a dual role as transcriptional promoters and enhancers, thus ensuring rapid and coordinate regulation of gene expression. These finding have important implications for the understanding of complex gene regulation in normal development and disease.

Publications associées:

L. Vanhille, A. Griffon, M. A. Maqbool, J. Zacarias-Cabeza, L. T. Dao, N. Fernandez, B. Ballester, J. C. Andrau, and S. Spicuglia. High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq (2015). Nat Commun. 6:6905, 2015.

Dao LTM, Galindo-Albarrán AO, Castro-Mondragon JA, Andrieu-Soler C, Medina-Rivera A, Souaid C, Charbonnier G, Griffon A, Vanhille L, Stephen T, Alomairi J, Martin D, Torres M, Fernandez N, Soler E, van Helden J, Puthier D, Spicuglia S (2017). Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat Genet. 49(7):1073-1081. PMID: 28581502.