Journal article
A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway
Cell (Cambridge), Vol.155(5), pp.1022-1033
11/21/2013
DOI: 10.1016/j.cell.2013.10.022
PMCID: PMC3873608
PMID: 24267888
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.
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•Sequence variation in IRF4 is associated with pigmentation features including freckles•This sequence is located in an enhancer element that affects expression of IRF4•The transcription factors MITF and TFAP2A regulate expression from this element•Together, MITF and IRF4 affect regulation of the pigmentation enzyme TYR
A polymorphism in a noncoding region of IRF4, a transcription factor involved in immune signaling, is found to affect human pigmentation. This polymorphism affects the ability of the transcription factors TFAP2A and MITF to regulate IRF4 levels, which in turn results in reduced levels of the pigmentation enzyme Tyrosinase.
Details
- Title: Subtitle
- A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway
- Creators
- Christian Praetorius - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandChristine Grill - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandSimon N Stacey - Decode Genetics, Sturlugata 8, 101 Reykjavik, IcelandAlexander M Metcalf - Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, AustraliaDavid U Gorkin - McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USAKathleen C Robinson - Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USAEric Van Otterloo - Anatomy and Cell Biology, University of Iowa, 357 Medical Research Center, Iowa City, IA 52242-1101, USAReuben S.Q Kim - Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, AustraliaKristin Bergsteinsdottir - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandMargret H Ogmundsdottir - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandErna Magnusdottir - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandPravin J Mishra - Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892, USASean R Davis - Genetics Branch, National Cancer Institute, Building 37, Room 6138, 37 Convent Drive, Bethesda, MD 20892, USATheresa Guo - Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892, USAM. Raza Zaidi - Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892, USAAgnar S Helgason - Decode Genetics, Sturlugata 8, 101 Reykjavik, IcelandMartin I Sigurdsson - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, IcelandPaul S Meltzer - Genetics Branch, National Cancer Institute, Building 37, Room 6138, 37 Convent Drive, Bethesda, MD 20892, USAGlenn Merlino - Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Room 5002, 37 Convent Drive, Bethesda, MD 20892, USAValerie Petit - Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, Orsay 91405, FranceLionel Larue - Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, Orsay 91405, FranceStacie K Loftus - Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USADavid R Adams - Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAUlduz Sobhiafshar - Laboratory of Genome Regulation, Department of Molecular Biology and Genetics, Boğaziçi University, Bebek 34342, Istanbul, TurkeyN.C. Tolga Emre - Laboratory of Genome Regulation, Department of Molecular Biology and Genetics, Boğaziçi University, Bebek 34342, Istanbul, TurkeyWilliam J Pavan - Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USARobert Cornell - Anatomy and Cell Biology, University of Iowa, 357 Medical Research Center, Iowa City, IA 52242-1101, USAAaron G Smith - Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, AustraliaAndrew S McCallion - McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USADavid E Fisher - Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USAKari Stefansson - Decode Genetics, Sturlugata 8, 101 Reykjavik, IcelandRichard A Sturm - Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, AustraliaEirikur Steingrimsson - Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
- Resource Type
- Journal article
- Publication Details
- Cell (Cambridge), Vol.155(5), pp.1022-1033
- DOI
- 10.1016/j.cell.2013.10.022
- PMID
- 24267888
- PMCID
- PMC3873608
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 11/21/2013
- Academic Unit
- Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research; Periodontics
- Record Identifier
- 9984025343202771
Metrics
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