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Dissecting the Genome-wide Action of Interferon Regulatory Factor 4 (IRF4) in Melanoma

Final Report Summary - ONCOGENEREGULATION (Dissecting the Genome-wide Action of Interferon Regulatory Factor 4 (IRF4) in Melanoma)

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in lymphocyte development and function. In previous studies, high IRF4 expression was observed in melanoma type skin cancers, and genome wide association studies implicated IRF4-linked variants to pigmentation phenotypes and skin cancers. However, the extent and molecular mechanisms of the role of IRF4 in melanoma has not been reported. In this project, we aimed to understand the role of IRF4 in melanoma cells using cellular, molecular, and genome-wide methodologies. The insights gained from the results of this project is intended to provide us with improved understanding into the melanoma biology, and point to novel therapeutic targets.
In the first two years, we have initiated the Phase I of the project, which involved setting up the laboratory infrastructure and the gene delivery system for melanoma cell lines, and testing the requirement for IRF4 in melanoma cell line survival and/or proliferation using RNA interference. We have confirmed IRF4 expression in melanoma both by re-analysis of published data, and in house experiments. We have also initiated the Phase II of the project that aimed to characterize the genes and pathways controlled by IRF4 in melanoma cells.
In final two years of the project we started characterizing the genes and pathways regulated by IRF4 in melanoma using genome-wide gene expression profiling and genome-wide localization assays. We have also confirmed a subset of these targets using gene-specific assays. In parallel, we aimed to clarify the consequences of reducing IRF4 levels in melanoma cells.
Our studies to date suggest that IRF4 is a critical factor for melanoma survival/proliferation at the cellular level. We were also able to take first glimpses at the gene regulatory network controlled by IRF4 in melanoma cells using genome-wide gene expression profiling and localization studies, and implicate several genes and pathways that may explain the critical role of IRF4 in melanoma cells.
Overall, this project was also instrumental in the establishment of the Laboratory of Genome Regulation ( at Bogazici University, which has contributed to tranfer of genomic technologies to the host institute, and to training of researchers.