Eprom · Epromoters in health and disease

Epromoters in health and disease

Regulation of gene transcription in higher eukaryotes is accomplished through the involvement of transcription start site proximal (promoters) and -distal (enhancers) regulatory elements. It is well established that enhancers play an essential role during development and cell differentiation, while genetic alterations in these elements are a major cause of human disease. The classical definition of enhancers implies the property to activate gene expression at a distance, while promoters induce local gene expression. However, this basic dichotomy has been challenged by broad similarities between them, which leads to the question what distinguishes enhancer and promoter function? Using a technique called CapSTARR-seq, which captures regions of interest (promoters) which are then tested for enhancer function in a high-throughput manner, the host team demonstrated that a subset of promoters, termed Epromoters, not only work as promoters, but also as bona fide enhancers, regulating expression of a distal gene as well. These Epromoters seem to regulate gene expression in several organisms from drosophila to humans. It was also found that Epromoters might play an essential role in the coordination of rapid gene induction during the inflammatory response. Therefore, we hypothesize that Epromoters work as a hub for recruiting the essential transcription factors (TFs) required for gene activation in different stress conditions and thus ensure a rapid coordinated expression response of several distal genes simultaneously (Figure 1). In addition to Epromoters, we are interested in human variation, or single nucleotide polymorphisms (SNPs). In recent years, common SNPs have been associated with susceptibility to several diseases and traits by genome-wide association studies (GWAS). Interestingly, most SNPs associated to pathology lie in the non-coding or regulatory genome, i.e. in enhancer or promoter regions. The discovery of Epromoters opens a new paradigm in the study of regulatory variants, as a SNP in a promoter could potentially influence the expression of several genes or change the relative ratio of promoter versus enhancer activity, thus potentially elucidating new disease mechanisms. This led to our project, identifying new Epromoters in the immune response, finding common (disease-associated) variants that are located in Epromoter, and characterizing the impact of these variants on enhancer versus promoter function.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз