Objetivo
Promoters and enhancers regulate transcription in higher eukaryotes. The classical definition of enhancers is the property to activate gene expression distally, while promoters induce local gene expression. However, itPromoters and enhancers regulate transcription in higher eukaryotes. The classical definition of enhancers is the property to activate gene expression distally, while promoters induce local gene expression. However, it was demonstrated that a subset of promoters, termed Epromoters, also work as bona fide enhancers and regulate distal gene expression. Moreover, it was shown that human single nucleotide polymorphisms (SNP) within Epromoters can influence their function, and consequently distal and proximal gene expression of their target genes. We hypothesise that Epromoters might have an unanticipated key role in coordinating gene expression in disease as well.
In this project, I will develop a dual reporter assay to investigate the enhancer versus promoter function of candidate regions, in order to identify novel Epromoters. Subsequently, selecting candidate Epromoters predicted by a previously developed bioinformatics pipeline, I will use the reporter assay to test the candidates in a high-throughput manner. Moreover, I will select those validated Epromoters that contain human disease associated SNPs using genome-wide association studies databases. Next, to determine which of these disease-associated SNPs have an impact on gene expression through Epromoter function, distally regulated genes will be inferred by genome editing of the identified SNPs in relevant cell lines.
Concluding, I will study the biology of Epromoters by i) analysing their function in physiological context, ii) assessing the impact of overlapping genetic variants, and iii) determining the effect of disease-associated SNPs on Epromoters and their target gene expression, thus providing a valuable resource to understand Epromoters and their potential involvement in different diseases.
Ámbito científico
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-AG-UN - HORIZON Unit GrantCoordinador
75654 Paris
Francia