Interferon Regulatory Factors; TFAP2A protein, human; Transcription Factor AP-2; interferon regulatory factor-4; Animals; Base Sequence; Enhancer Elements, Genetic; Humans; Interferon Regulatory Factors/chemistry; Interferon Regulatory Factors/genetics; Interferon Regulatory Factors/metabolism; Melanocytes/metabolism; Mice; Molecular Sequence Data; Pigmentation; Signal Transduction; Transcription Factor AP-2/chemistry; Transcription Factor AP-2/metabolism; Zebrafish; Polymorphism, Single Nucleotide; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Praetorius, Christian; Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
Grill, Christine ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling ; Department of Biochemistry and Molecular Biology, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
Stacey, Simon N; Decode Genetics, 101 Reykjavik, Iceland
Metcalf, Alexander M; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Gorkin, David U; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States ; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Robinson, Kathleen C; Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
Van Otterloo, Eric; Anatomy and Cell Biology, University of Iowa, 357 Medical Research Center, Iowa City, IA 52242-1101, United States
Kim, Reuben S Q; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia ; School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia
Bergsteinsdottir, Kristin; Department of Biochemistry and Molecular Biology, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
Ogmundsdottir, Margret H; Department of Biochemistry and Molecular Biology, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
Magnusdottir, Erna; Department of Biochemistry and Molecular Biology, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
Mishra, Pravin J; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Davis, Sean R; Genetics Branch, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Guo, Theresa; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Zaidi, M Raza; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Sigurdsson, Martin I; Department of Biochemistry and Molecular Biology, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
Meltzer, Paul S; Genetics Branch, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Merlino, Glenn; Laboratory of Cancer Biology and Genetics, National Cancer Institute, Building 37, Bethesda, MD 20892, United States
Petit, Valerie; Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, Orsay 91405, France
Larue, Lionel; Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, Orsay 91405, France
Loftus, Stacie K; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Adams, David R; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Sobhiafshar, Ulduz; Laboratory of Genome Regulation, Department of Molecular Biology and Genetics, Boǧaziçi University, Bebek 34342, Istanbul, Turkey
Emre, N C Tolga; Laboratory of Genome Regulation, Department of Molecular Biology and Genetics, Boǧaziçi University, Bebek 34342, Istanbul, Turkey
Pavan, William J; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
Cornell, Robert; Anatomy and Cell Biology, University of Iowa, 357 Medical Research Center, Iowa City, IA 52242-1101, United States
Smith, Aaron G; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia ; School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia
McCallion, Andrew S; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Fisher, David E; Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
We thank Thorunn Rafnar, Magnus Karl Magnusson, Unnur Thorsteinsdottir, Colin R. Goding, and Thorarinn Gudjonsson for critical comments on the manuscript. This work was supported by grants from NIH (5R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon Adelson Medical Research Foundation, US-Israel Binational Science Foundation (to D.E.F.), Ligue Nationale Contre le Cancer (Equipe labellisée) and INCa (to L.L.), the Icelandic Research Fund and the Research Fund of the University of Iceland (to E.S.), the Haskolasjodur Student Fund (to E.S., C.P., and C.G.), the Jules Verne Fund (to E.S. and L.L.), by the National Institute of General Medical Sciences (GM071648) and National Institute of Neurological Disease and Stroke (NS062972; to A.S.M.), the National Human Genome Research Institute’s Intramural Research Program (to W.J.P. and S.L.), and an NSF Graduate Research Fellowship (to D.U.G.).
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