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MHI Seminar Series presents Jonathan Brown, MD, Riven Family Director of Experimental Biology at Vanderbilt University Medical Center
April 17 @ 10:00 am - 11:00 am
Summary of Seminar: Combinatorial signaling by proinflammatory cytokines synergizes to exacerbate toxicity to cells and tissue injury in both acute and chronic cardiovascular disease. To explore synergism at the gene regulatory level, we investigated the dynamics of transcription and chromatin signaling in response to dual cytokines by integrating nascent RNA imaging mass spectrometry, RNA-sequencing, amplification-independent mRNA quantification, ATAC-sequencing and transcription factor profiling. Co-stimulation with interferon-gamma (IFNγ) and tumor necrosis-alpha (TNFα) synergistically induced a small subset of genes, including the chemokines CXCL9, -10, -11. Gene induction coincided with increased chromatin accessibility at non-coding regions enriched for p65 and STAT1 binding sites. To discover coactivator dependencies, we conducted a targeted chemogenomic screen of transcriptional inhibitors, followed by modelling of inhibitor dose-response curves. These results identified high efficacy of either p300/CBP or BET bromodomain inhibitors to disrupt induction of synergy genes. Combination p300/CBP and BET bromodomain inhibition at subIC50 concentrations synergistically abrogated IFNγ/TNFα-induced chemokine gene and protein levels.
UNC Lineberger Comprehensive Cancer Center, Pagano Conference Room (LCCC 00-002)
450 West Dr.
Chapel Hill, North Carolina 27599
United States
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