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A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway

2013; Cell Press; Volume: 155; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2013.10.022

1097-4172

Christian Praetorius, Christine Grill, Simon Stacey, Alexander M. Metcalf, David U. Gorkin, Kathleen C. Robinson, Eric Van Otterloo, Reuben S.Q. Kim, Kristín Bergsteinsdóttir, Margrét H. Ögmundsdóttir, Erna Magnúsdóttir, Pravin J. Mishra, Sean Davis, Theresa Guo, M. Raza Zaidi, Agnar Helgason, Martin I. Sigurðsson, Paul S. Meltzer, Glenn Merlino, Valérie Petit, Lionel Larue, Stacie K. Loftus, David R. Adams, Ulduz Sobhiafshar, N. C. Tolga Emre, William J. Pavan, Robert A. Cornell, Aaron G. Smith, Andrew S. McCallion, David E. Fisher, Kāri Stefánsson, Richard A. Sturm, Eirı́kur Steingrı́msson,

Skin Protection and Aging

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.