ZFIN ID: ZDB-PUB-140108-7
A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway
Praetorius, C., Grill, C., Stacey, S.N., Metcalf, A.M., Gorkin, D.U., Robinson, K.C., Van Otterloo, E., Kim, R.S., Bergsteinsdottir, K., Ogmundsdottir, M.H., Magnusdottir, E., Mishra, P.J., Davis, S.R., Guo, T., Zaidi, M.R., Helgason, A.S., Sigurdsson, M.I., Meltzer, P.S., Merlino, G., Petit, V., Larue, L., Loftus, S.K., Adams, D.R., Sobhiafshar, U., Emre, N.C., Pavan, W.J., Cornell, R., Smith, A.G., McCallion, A.S., Fisher, D.E., Stefansson, K., Sturm, R.A., and Steingrimsson, E.
Date: 2013
Source: Cell   155(5): 1022-1033 (Journal)
Registered Authors: Cornell, Robert, McCallion, Andy
Keywords: none
MeSH Terms:
  • Animals
  • Base Sequence
  • Enhancer Elements, Genetic
  • Humans
  • Interferon Regulatory Factors/chemistry
  • Interferon Regulatory Factors/genetics
  • Interferon Regulatory Factors/metabolism*
  • Melanocytes/metabolism
  • Mice
  • Molecular Sequence Data
  • Pigmentation
  • Polymorphism, Single Nucleotide*
  • Signal Transduction
  • Transcription Factor AP-2/chemistry
  • Transcription Factor AP-2/metabolism
  • Zebrafish
PubMed: 24267888 Full text @ Cell

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.