Investigating the Link Between REV-ERB and HIF-1a in Th17 Cell Function

Abstract ID 128383 Poster Board 563 Autoimmune diseases affect a significant population within the United States and worldwide. A common factor among these diseases is the activation of IL-17A expressing T-cells, specifically Th17 cells, that are thought to have evolved for host protection from microbes but play an important role in the functioning of the adaptive immune system in humans. Dysregulation of Th17 cells have been implicated in the pathogenesis of autoimmune diseases including Multiple Sclerosis, rheumatoid arthritis, and colitis, but have also been shown to be a promising drug target for cancer immunotherapies as well. The regulation of Th17 cells (differentiation and activation) are under the control of many transcription factors including RORgt and HIF-1a. HIF-1a enhances Th17 cell activation through transcriptional activation of RORgt and can also form a complex with RORgt and p300 at the IL-17 promoter to induce Th17 cell activation. HIF-1a has been identified as an integral factor in the regulation of T-cell/Th17 cell balance in studies with HIF-1a-null mice. These mice are resistant to Th17 cell mediated experimental autoimmune encephalitis (EAE) and highlighted the role that HIF-1a regulated metabolic pathways play in autoimmune diseases. The nuclear receptor REV-ERB (NR1D1 and NR1D2) competes with RORgt for binding to the response element of ROR-regulated genes within immune cells to repress gene transcription. REV-ERB and ROR act like a "yin and yang" of transcriptional regulation in that they are interconnected (by feedback mechanisms and regulatory components) and regulate the expression of target genes in opposing ways. Genes that are upregulated by ROR are downregulated by REV-ERB, including IL-17. Interestingly, REV-ERB can also recognize a specific response element in some genes that ROR cannot bind to called the REV-RE, suggesting that REV-ERB not only competes with ROR for regulating gene transcription but also has a subset of genes that are solely regulated by REV-ERB. We found a putative REV-RE within the promoter region of HIF-1a (just upstream of exon 1) that has significant occupancy of REV-ERB based on ChIP-Seq studies. Our goal is to identify the molecular mechanisms of REV-ERB's regulation of Th17 cell driven autoimmune disease. We are using a chemical biology approach to determine whether HIF-1a is under direct regulation of REV-ERB and the molecular mechanisms that support REV-ERB as a therapeutic target for autoimmune diseases. This work is funded by NIH National Institute of Allergy and Infectious Diseases 1R03AI177835.