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

Summary

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 nevus count in European-derived populations. We have characterised 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.

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