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Cell. 2013 Nov 21;155(5):1022-33. doi: 10.1016/j.cell.2013.10.022.

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

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  • 1Department of Biochemistry and Molecular Biology, Biomedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland.

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.

Copyright © 2013 Elsevier Inc. All rights reserved.

Comment in

  • SNPing away at human skin color. [Pigment Cell Melanoma Res. 2014]
PMID:
24267888
[PubMed - indexed for MEDLINE]
PMCID:
PMC3873608
Free PMC Article
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