ONCOGENEREGULATION · Dissecting the Genome-wide Action of Interferon Regulatory Factor 4 (IRF4) in Melanoma
FP7 — People (Marie Curie Actions)
- Duration
- 2011-08-01 → 2015-07-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
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 (genreg.boun.edu.tr) at Bogazici University, which has contributed to tranfer of genomic technologies to the host institute, and to training of researchers.
Data: CORDIS, © European Union
Project objective
Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in lymphocyte development and function. We have recently shown that cells from a poor-prognosis subtype of lymphoma and multiple myeloma show non-oncogene addiction to IRF4. Using integrative genome-wide strategies, we have identified the gene regulatory program that IRF4 controls in these cancers.In several studies, high IRF4 expression was consistently observed also in cells derived from the melanoma type skin cancers at both mRNA and protein level. A survey of multiple gene expression profiling studies show that IRF4 expression is significantly high in melanoma. In addition, several genome-wide association studies identified IRF4-linked polymorphisms contributing to pigmentation, nevi count and risk of developing melanoma. These studies, taken together with our first-hand understanding of IRF4’s crucial role in B-cell cancers, strongly implicate a direct role for IRF4 in melanoma. However, the extent and molecular mechanisms of the role of IRF4 in melanoma and melanocyte biology have so far not been reported.We are initiating a project to study the role of IRF4 in melanoma cells using cellular, molecular, and genome-wide approaches as the first segment of my research program aimed at investigating the critical gene regulatory and epigenetic networks in cancers. Specifically, we will study the requirement of IRF4 in the tumorigenicity of melanoma cells. Further, we aim to employ genome-wide expression and localization (ChIP-Seq) assays to identify the genes and downstream pathways controlled by IRF4 in melanoma, and test their roles in melanoma development and progression. Melanoma incidence has been on the rise, and advanced forms of melanoma are mostly resistant to current therapies, and deadly. This project is aimed at improving understanding of melanoma biology, and identification of novel genes and pathways that can ultimately be targeted for therapy.
Original text from CORDIS.
Participants
- BOGAZICI UNIVERSITESI · IstanbulCoordinatorTürkiye
Links
Data: CORDIS, © European Union