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

Praetorius, Christian, Grill, Christine, Stacey, Simon N., Metcalf, Alexander M., Gorkin, David U., Robinson, Kathleen C., Van Otterloo, Eric, Kim, Reuben S. Q., Bergsteinsdottir, Kristin, Ogmundsdottir, Margret H., Magnusdottir, Erna, Mishra, Pravin J., Davis, Sean R., Guo, Theresa, Zaidi, M. Raza, Helgason, Agnar S., Sigurdsson, Martin I., Meltzer, Paul S., Merlino, Glenn, Petit, Valerie, Larue, Lionel, Loftus, Stacie K., Adams, David R., Sobhiafshar, Ulduz, Emre, N.C. Tolga, Pavan, William J., Cornell, Robert, Smith, Aaron G., McCallion, Andrew S., Fisher, David E., Stefansson, Kari, Sturm, Richard A. and Steingrimsson, Eirkur (2013) A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 155 5: 1022-1033. doi:10.1016/j.cell.2013.10.022

Author Praetorius, Christian
Grill, Christine
Stacey, Simon N.
Metcalf, Alexander M.
Gorkin, David U.
Robinson, Kathleen C.
Van Otterloo, Eric
Kim, Reuben S. Q.
Bergsteinsdottir, Kristin
Ogmundsdottir, Margret H.
Magnusdottir, Erna
Mishra, Pravin J.
Davis, Sean R.
Guo, Theresa
Zaidi, M. Raza
Helgason, Agnar S.
Sigurdsson, Martin I.
Meltzer, Paul S.
Merlino, Glenn
Petit, Valerie
Larue, Lionel
Loftus, Stacie K.
Adams, David R.
Sobhiafshar, Ulduz
Emre, N.C. Tolga
Pavan, William J.
Cornell, Robert
Smith, Aaron G.
McCallion, Andrew S.
Fisher, David E.
Stefansson, Kari
Sturm, Richard A.
Steingrimsson, Eirkur
Title A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway
Journal name Cell   Check publisher's open access policy
ISSN 0092-8674
Publication date 2013-11-21
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.cell.2013.10.022
Open Access Status DOI
Volume 155
Issue 5
Start page 1022
End page 1033
Total pages 12
Place of publication Cambridge, United States
Publisher Cell Press
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
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.
Keyword Biochemistry & Molecular Biology
Cell Biology
Biochemistry & Molecular Biology
Cell Biology
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 5R01 AR043369-16
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 59 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 17 Dec 2013, 01:19:55 EST by Susan Allen on behalf of Institute for Molecular Bioscience