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


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.

SUBMITTER: Praetorius C 

PROVIDER: S-EPMC3873608 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Praetorius Christian C   Grill Christine C   Stacey Simon N SN   Metcalf Alexander M AM   Gorkin David U DU   Robinson Kathleen C KC   Van Otterloo Eric E   Kim Reuben S Q RS   Bergsteinsdottir Kristin K   Ogmundsdottir Margret H MH   Magnusdottir Erna E   Mishra Pravin J PJ   Davis Sean R SR   Guo Theresa T   Zaidi M Raza MR   Helgason Agnar S AS   Sigurdsson Martin I MI   Meltzer Paul S PS   Merlino Glenn G   Petit Valerie V   Larue Lionel L   Loftus Stacie K SK   Adams David R DR   Sobhiafshar Ulduz U   Emre N C Tolga NC   Pavan William J WJ   Cornell Robert R   Smith Aaron G AG   McCallion Andrew S AS   Fisher David E DE   Stefansson Kari K   Sturm Richard A RA   Steingrimsson Eirikur E  

Cell 20131101 5


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 associ  ...[more]

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