Mots-Clés

Genomics genetics gene regulation genetic variation

Description

Genes are transcriptionnally regulated by a combination of distal gene regulatory sequences and proximal promoters. Our and other laboratories have shown that gene promoters also exert a distal transcriptional regulatory function, also called enhancer activity, on different distal genes (10.1038/ng.3884). These gene promoters with distal activity have been called enhancer-promoter (ePromoters). Genetic variants found in the non-coding genome and overlapping cis-regulatory elements have the potential to influence gene expression.

We hypothesize that genetic variants overlapping Epromoters might have a pleiotropic impact on normal traits and disease by affecting the expression of proximal and distal genes at the same time. Frequent genetic mutations can be statistically associated to expression changes (expression quantitative trail loci or eQTLs) (10.1126/science.aaz1776) and chromatin histone acetylation changes (histone QTLs, hQTLs) (10.1038/s41467-018-05328-9).

In this internship, we would like to characterize eQTLs and hQTLs, along with high-throughput reporter assays, in order to infer how genetic variation might influence the enhancer and/or promoter activity of Epromoters. We are going to use human lymphoblastoid cells from different human individuals that have been sequenced and characterized in detail at the level of the genome (1000 Genomes database), transcriptome (10.1038/nature12531) and epigenome in different human individuals (10.1016/j.cell.2015.07.048). These integrative analyses might lead to a better understanding of how regulatory variants impact on gene expression.

- Genome-wide characterization of mammalian promoters with distal enhancer functions. DOI 10.1038/ng.3884. - The GTEx Consortium atlas of genetic regulatory effects across human tissues. DOI 10.1126/science.aaz1776. - Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. DOI 10.1038/s41467-018-05328-9 - Transcriptome and genome sequencing uncovers functional variation in humans. DOI 10.1038/nature12531 - Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions. DOI 10.1016/j.cell.2015.07.048