Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon-gamma response in melanocytic cells

Pigment Cell Melanoma Res. 2018 Jan;31(1):51-63. doi: 10.1111/pcmr.12620. Epub 2017 Oct 23.


A SNP within intron4 of the interferon regulatory factor4 (IRF4) gene, rs12203592*C/T, has been independently associated with pigmentation and age-specific effects on naevus count in European-derived populations. We have characterized the cis-regulatory activity of this intronic region and using human foreskin-derived melanoblast strains, we have explored the correlation between IRF4 rs12203592 homozygous C/C and T/T genotypes with TYR enzyme activity, supporting its association with pigmentation traits. Further, higher IRF4 protein levels directed by the rs12203592*C allele were associated with increased basal proliferation but decreased cell viability following UVR, an etiological factor in melanoma development. Since UVR, and accompanying IFNγ-mediated inflammatory response, is associated with melanomagenesis, we evaluated its effects in the context of IRF4 status. Manipulation of IRF4 levels followed by IFNγ treatment revealed a subset of chemokines and immuno-evasive molecules that are sensitive to IRF4 expression level and genotype including CTLA4 and PD-L1.

Keywords: MITF; IRF4; UVR response; interferon response; melanocyte; melanoma; tyrosinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism*
  • Interferon-gamma / pharmacology*
  • Melanocytes / drug effects
  • Melanocytes / metabolism
  • Melanocytes / pathology*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Monophenol Monooxygenase / metabolism*
  • Polymorphism, Single Nucleotide*
  • Ultraviolet Rays


  • Antiviral Agents
  • Interferon Regulatory Factors
  • interferon regulatory factor-4
  • Interferon-gamma
  • Monophenol Monooxygenase