Small-molecule ROR?t antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

ABSTRACT: We identified three retinoid-related orphan receptor gamma t (ROR?t)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized ROR?t binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. ROR?t 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 ROR? binding motif. ROR?t is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the ROR?t-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced ROR?t from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

SUBMITTER: Xiao S 

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

REPOSITORIES: biostudies-literature