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Pan G, Cavalli M, Carlsson B, Skrtic S, Kumar C, Wadelius C
iScience 23 (2) 100808 [2020-02-21; online 2020-01-09]
Long-chain polyunsaturated fatty acids (LC-PUFAs) influence human health in several areas, including cardiovascular disease, diabetes, fatty liver disease, and cancer. ELOVL2 encodes one of the key enzymes in the in vivo synthesis of LC-PUFAs from their precursors. Variants near ELOVL2 have repeatedly been associated with levels of LC-PUFA-derived metabolites in genome-wide association studies (GWAS), but the mechanisms behind these observations remain poorly defined. In this study, we found that rs953413, located in the first intron of ELOVL2, lies within a functional FOXA and HNF4α cooperative binding site. The G allele of rs953413 increases binding of FOXA1/FOXA2 and HNF4α to an evolutionarily conserved enhancer element, conferring allele-specific upregulation of the rs953413-associated gene ELOVL2. The expression of ELOVL2 was significantly downregulated by both FOXA1 and HNF4α knockdown and CRISPR/Cas9-mediated direct mutation to the enhancer element. Our results suggest that rs953413 regulates LC-PUFAs metabolism by altering ELOVL2 expression through FOXA1/FOXA2 and HNF4α cooperation.
Bioinformatics Support for Computational Resources [Service]
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 31928966
DOI 10.1016/j.isci.2019.100808
Crossref 10.1016/j.isci.2019.100808
pii: S2589-0042(19)30554-1
pmc: PMC7033636