Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

ABSTRACT: We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mecha

SUBMITTER: Xiao S 

PROVIDER: S-EPMC4066874 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature