IRF4-driven epigenetic changes in melanoma cells: Understanding downstream effects for targeted therapy

Despite recent advances in melanoma treatment, mortality rates for metastatic melanoma remain high, which indicates the need to identify new melanoma-critical genes and novel targeted therapies. Melanoma, like other cancers, is driven by driver mutations and the deregulation of epigenome and signaling pathways. Transcription factor IRF4 has been identified as a pivotal player in the development and maintenance of different cells, such as immune cells and melanocytes. Studies showed that IRF4 is an essential component of the survival and maintenance of hematopoietic cancers such as multiple myeloma. Different GWAS studies indicate a strong link between a variation in the IRF4 intronic region with pigmentation in melanocytes and predisposition to melanoma. In this thesis, analysis of patient data from The Cancer Genome Atlas and the integration of RNA-seq and ChIP-seq approaches have led to the identification of IRF4-regulated genes and pathways. Our data demonstrate that IRF4 is a modulator of epigenetic silencing in melanoma. Furthermore, we report that IRF4 is a key modulator of DNA methylation machinery and polycomb repressive complex, which subsequently results in global changes in the epigenetic suppressive marks in the cells. Also, we identify a subset of tumor suppressor genes (TSG) silenced through IRF4-mediated changes of these epigenetic marks. These TSGs are regulators of the cell cycle, PI3K-AKT pathway, and ciliogenesis in melanoma. Moreover, with CRISPR knockout screening, we set out to discover IRF4 synthetic lethal partners. Consistent with our findings, the screening results suggest a critical role for IRF4 as a regulator of the cell cycle and homeostasis pathways in melanoma cells.