Oral communication, PS8 / C103

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

The role of Interferon Regulatory Factor 4 (IRF4) in pigmentation

BACKGROUND AND OBJECTIVES: In a recent gene-expression analysis we identified the Interferon Regulatory Factor 4 (Irf4) gene as a potential target of Mitf in melanoma cells. The Irf4 gene encodes a transcription factor which acts as a lineage survival oncogene in multiple myeloma. Genome-wide association studies in humans have shown that polymorphisms in the IRF4 gene are associated with fair skin and light/blue eye color, suggesting that the gene plays an important role in melanocytes. METHODS: Effects of Mitf on Irf4 gene expression were investigated using Mitf mutant mice and siRNA studies in melanocyte and melanoma cell lines. ChIP studies were used to investigate presence of the MITF protein on the Irf4 promoter and reporter gene assays to investigate effects of MITF on the Irf4 promoter and the synergistic effects of MITF and IRF4 on Tyrosinase expression. RESULTS: Irf4 gene expression is dependent on MITF. This is shown both by the absence of Irf4 expression in Mitf mutant mice and by significant reduction of Irf4 gene expression upon Mitf reduction using siRNA. ChIP studies show that the MITF protein binds regulatory sequences in IRF4 intron 4, near a polymorphism that has been associated with skin and eye color. Importantly, the IRF4 and MITF proteins synergistically regulate the expression of the pigmentation gene Tyrosinase but not of several other melanocyte specific genes. Mutating the IRF4 binding sites in Tyrosinase eliminates this synergistic effect. CONCLUSION: We have shown that Irf4 expression in pigment cells depends on Mitf and that together, the MITF and IRF4 proteins affect the regulation of the Tyrosinase promoter. This may explain the pigmentation phenotype in humans.

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