title: PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c.
abstract: The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1. The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Gang
authors.initials: G
authors.lastname: Pan
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Bysani
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Nord
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Cavalli
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75237, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Wadelius
mesh_terms: D000483:Alleles; D020087:Alu Elements; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D000090943:Delta-5 Fatty Acid Desaturase; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D002679:Pan troglodytes; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D051741:Kruppel-Like Transcription Factors; C412784:PATZ1 protein, human; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human