摘要：SummaryLong-chain polyunsaturated fatty acids (LC-PUFAs) influence human health in several areas, including cardiovascular disease, diabetes, fatty liver disease, and cancer.ELOVL2encodes one of the key enzymes in thein vivosynthesis of LC-PUFAs from their precursors. Variants nearELOVL2have 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 ofELOVL2, 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 geneELOVL2. The expression ofELOVL2was significantly downregulated by bothFOXA1andHNF4αknockdown and CRISPR/Cas9-mediated direct mutation to the enhancer element. Our results suggest that rs953413 regulates LC-PUFAs metabolism by alteringELOVL2expression through FOXA1/FOXA2 and HNF4α cooperation.Graphical AbstractDisplay OmittedHighlights•rs953413 resides in an evolutionarily conserved enhancer region•rs953413 mediates the cooperative binding of FOXA and HNF4α to the enhancer region•The rs953413 locus plays a key role in regulatingELOVL2expression•rs953413 is implicated in PUFA metabolism by regulatingELOVL2expressionHealth Sciences; Biological Sciences; Genetics; Molecular Genetics; Molecular Biology; Molecular Mechanism of Gene Regulation
