Defining REV-ERBα’s ligand-mediated transcriptional mechanisms in TH17 cells 2535

Abstract Description TH17 cells are a subset of CD4+ T cells that mediate autoimmune and chronic inflammatory pathology. We have demonstrated that REV-ERBα, a member of the nuclear receptor superfamily of ligand-regulated transcription factors, acts as a critical repressor of this cell type. In line with this finding, REV-ERB agonism has been shown to ameliorate disease in several mouse models of chronic inflammation. Much work has been done to identify the target genes of REV-ERBα across multiple tissues. However, little is known about the transcriptional machinery driving its function. Our goal is to identify key proteins that drive REV-ERBα-mediated gene repression in pathogenic TH17 cells and further understand how ligands modulate this process. Therefore, we have performed miniTurboID proximity labeling and subsequent proteomic analysis to capture the REV-ERBα interactome in TH17 cells. Comparison of the REV-ERBα interactome induced by the presence and absence of endogenous ligand binding will provide insight into the transcriptional complexes that mediate REV-ERBα activity and the role of ligands in their formation. Ultimately, these efforts will bolster our understanding of REV-ERB and TH17 biology and inform the development of focused therapeutics for TH17-mediated autoimmune and chronic inflammatory diseases. Funding Sources Supported by NIH R01 DK135300 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)