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Genetic variation in IRF 4 expression modulates growth characteristics, tyrosinase expression and interferon‐gamma response in melanocytic cells
Author(s) -
Chhabra Yash,
Yong Hilary X.L.,
Fane Mitchell E.,
Soogrim Arish,
Lim Wen,
Mahiuddin Dayaur,
Kim Reuben S.Q.,
Ashcroft Melinda,
Beatson Scott A.,
Ainger Stephen A.,
Smit Darren J.,
Jagirdar Kasturee,
Walker Graeme J.,
Sturm Richard A.,
Smith Aaron G.
Publication year - 2018
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12620
Subject(s) - irf4 , biology , allele , context (archaeology) , interferon regulatory factors , genotype , microphthalmia associated transcription factor , melanocyte , gene , cancer research , microbiology and biotechnology , genetics , melanoma , transcription factor , paleontology
Summary A SNP within intron4 of the interferon regulatory factor4 ( IRF 4 ) 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 IRF 4 rs12203592 homozygous C/C and T/T genotypes with TYR enzyme activity, supporting its association with pigmentation traits. Further, higher IRF 4 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 IFN γ‐mediated inflammatory response, is associated with melanomagenesis, we evaluated its effects in the context of IRF 4 status. Manipulation of IRF 4 levels followed by IFN γ treatment revealed a subset of chemokines and immuno‐evasive molecules that are sensitive to IRF 4 expression level and genotype including CTLA 4 and PD ‐L1 .