title: A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway.
abstract: Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland.
authors.forename: Christian
authors.initials: C
authors.lastname: Praetorius
authors.forename: Christine
authors.initials: C
authors.lastname: Grill
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Metcalf
authors.forename: David U
authors.initials: DU
authors.lastname: Gorkin
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Robinson
authors.forename: Eric
authors.initials: E
authors.lastname: Van Otterloo
authors.forename: Reuben S Q
authors.initials: RS
authors.lastname: Kim
authors.forename: Kristin
authors.initials: K
authors.lastname: Bergsteinsdottir
authors.forename: Margret H
authors.initials: MH
authors.lastname: Ogmundsdottir
authors.forename: Erna
authors.initials: E
authors.lastname: Magnusdottir
authors.forename: Pravin J
authors.initials: PJ
authors.lastname: Mishra
authors.forename: Sean R
authors.initials: SR
authors.lastname: Davis
authors.forename: Theresa
authors.initials: T
authors.lastname: Guo
authors.forename: M Raza
authors.initials: MR
authors.lastname: Zaidi
authors.forename: Agnar S
authors.initials: AS
authors.lastname: Helgason
authors.forename: Martin I
authors.initials: MI
authors.lastname: Sigurdsson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.forename: Valerie
authors.initials: V
authors.lastname: Petit
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.forename: Ulduz
authors.initials: U
authors.lastname: Sobhiafshar
authors.forename: N C Tolga
authors.initials: NC
authors.lastname: Emre
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Robert
authors.initials: R
authors.lastname: Cornell
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Smith
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Sturm
authors.forename: Eirikur
authors.initials: E
authors.lastname: Steingrimsson
mesh_terms: D000818:Animals; D001483:Base Sequence; D004742:Enhancer Elements, Genetic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010858:Pigmentation; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000737:chemistry / Q000378:metabolism; D015027:Zebrafish; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D050656:Transcription Factor AP-2; D000099218:Interferon Regulatory Factor-4; C493673:TFAP2A protein, human