Genetic variation in IRF4 expression modulates growth characteristics,tyrosinase expression and interferon‐gamma response in melanocytic cells |
| |
| Authors: | Yash Chhabra Hilary XL Yong Mitchell E Fane Arish Soogrim Wen Lim Dayana Nur Mahiuddin Reuben SQ Kim Melinda Ashcroft Scott A Beatson Stephen A Ainger Darren J Smit Kasturee Jagirdar Graeme J Walker Richard A Sturm Aaron G Smith |
| |
| Institution: | 1. Dermatology Research Centre, UQ Diamantina Institute, The University of Queensland, TRI, Brisbane, QLD, Australia;2. School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, at the Translational Research Institute, Brisbane, QLD, Australia;3. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia;4. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia;5. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;6. Dermatology Research Centre, UQ Diamantina Institute, The University of Queensland, TRI, Brisbane, QLD, AustraliaEqual author contribution.;7. School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, at the Translational Research Institute, Brisbane, QLD, AustraliaEqual author contribution. |
| |
| Abstract: | 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: | interferon response IRF4 melanocyte melanoma
MITF
tyrosinase UVR response |
|
|
