rs953413 Regulates Polyunsaturated Fatty Acid Metabolism by Modulating ELOVL2 Expression

• Main Authors: Gang Pan, Marco Cavalli, Björn Carlsson, Stanko Skrtic, Chanchal Kumar, Claes Wadelius
• Format: Article
• Language: English
• Published: Elsevier 2020-02-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004219305541

Summary: 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. : Health Sciences; Biological Sciences; Genetics; Molecular Genetics; Molecular Biology; Molecular Mechanism of Gene Regulation Subject Areas: Health Sciences, Biological Sciences, Genetics, Molecular Genetics, Molecular Biology, Molecular Mechanism of Gene Regulation