Genome-wide Identification of IRF1 Binding Sites Reveals Extensive Occupancy at Cell Death Associated Genes.

Abstract

IRF1 is a transcription factor involved in interferon signaling and has been shown to harbor tumor suppressor activity. In order to comprehensively identify pathways regulated by IRF1, we used chromatin immunoprecipitation followed by massive-parallel sequencing (ChIP-seq) to evaluate the gene targets of IRF1 genome-wide. We identified 17,416 total binding events in breast cancer cells. Functional categorization of the binding sites after IFN-gamma (interferon-gamma) treatment determined that ‘apoptosis’ or ‘cell death’ is the most enriched target process. Motif discovery analysis of the chromosomal regions bound by IRF1 identified a number of unique motifs correlated with apoptosis, DNA damage and immune processes. Analysis of GEO transcriptome data from IRF1-transduced cells or IFN-gamma treated fibroblasts indicates that IRF1-bound targets in IFN-treated cells are associated with a positive transcriptional response. Many of the enriched target genes from the expression analysis are associated with apoptosis. Importantly, this data indicates that a significant function of IRF1 is the regulation of anti-cancer apoptotic pathways and this reinforces IRF1’s role as a tumor suppressor.