XA polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway

Christian Praetorius, Christine Grill, Simon N. Stacey, Alexander M. Metcalf, David U. Gorkin, Kathleen C. Robinson, Eric Van Otterloo, Reuben S.Q. Kim, Kristin Bergsteinsdottir, Margret H. Ogmundsdottir, Erna Magnusdottir, Pravin J. Mishra, Sean R. Davis, Theresa Guo, M. Raza Zaidi, Agnar S. Helgason, Martin I. Sigurdsson, Paul S. Meltzer, Glenn Merlino, Valerie PetitLionel Larue, Stacie K. Loftus, David R. Adams, Ulduz Sobhiafshar, N. C.Tolga Emre, William J. Pavan, Robert Cornell, Aaron G. Smith, Andrew S. McCallion, David E. Fisher, Kari Stefansson, Richard A. Sturm, Eirikur Steingrimsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1022-1033
Issue number5
Publication statusPublished - 21 Nov 2013

Bibliographical note

Funding Information:
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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