"Investigating the Regulation of TNFα/IFNγ Synergy by Transcriptional Coativators in Endothelial Cells"

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Project Summary Atherosclerosis is the culmination of a chronic inflammatory response to endothelial cell injury. Central to the initiation and progression of atherosclerotic plaques are cytokines, signaling molecules which are secreted by and act on leukocytes, endothelial cells, and vascular smooth muscle cells. In particular, human atherosclerotic plaques exhibit an increase in several members of the interleukin family, TNFα, and IFNγ. TNFα and IFNγ have been shown to induce a greater than additive level of expression of key mediators of atherosclerosis, including adhesion molecules, chemokines, and components of antigen presentation pathways. While transcriptional synergy is traditionally viewed as the product of cooperative transcription factor binding at cis-regulatory elements, it is possible for synergism to be induced via control of rate limiting steps in the transcription cycle. These steps, primarily RNA polymerase recruitment and pause release, are controlled by transcriptional coactivators which are emerging as critical links between transcription factor binding and target gene control. We hypothesize that TNFα/IFNγ induced synergistic gene expression is mediated via kinetic regulation of the transcriptional cycle, that this involves increased recruitment of multiple coactivators, and that synergistic gene induction can be selectively perturbed via combination treatment with small molecule inhibitors of these coactivators. If true, we believe this represents a promising target and therapeutic strategy in the treatment of atherosclerosis. We plan to utilize high-throughout sequencing techniques including RNA-sequencing and Chip- sequencing to characterize the transcriptional and epigenetic mechanisms involved in synergistic gene induction along with a chemical biology approach to perturb likely protein mediators of this process.