iScience
Volume 23, Issue 2, 21 February 2020, 100808
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Article
rs953413 Regulates Polyunsaturated Fatty Acid Metabolism by Modulating ELOVL2 Expression

https://doi.org/10.1016/j.isci.2019.100808Get rights and content
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Highlights

  • 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 regulating ELOVL2 expression

  • rs953413 is implicated in PUFA metabolism by regulating ELOVL2 expression

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.

Subject Areas

Health Sciences
Biological Sciences
Genetics
Molecular Genetics
Molecular Biology
Molecular Mechanism of Gene Regulation

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