s-3483 and Multiple-Sclerosis

The transcription factor retinoid-related orphan receptor gamma t (RORγt) has emerged as an exciting target for inflammatory diseases. Xiao et al. (2014) show that a new class of RORγt antagonists can inhibit the inflammatory function of T helper 17 cells without altering RORγt occupancy on its target genes.

Topics: Animals; Benzeneacetamides; Benzhydryl Compounds; Digoxin; Encephalomyelitis, Autoimmune, Experimental; Gene Regulatory Networks; Heterocyclic Compounds, 4 or More Rings; Humans; Multiple Sclerosis; Nuclear Receptor Subfamily 1, Group F, Member 3; T-Lymphocyte Subsets; Th17 Cells

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 mechanisms. Whereas one inhibitor displaced RORγt 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.

Topics: Androstenols; Animals; Benzeneacetamides; Benzhydryl Compounds; Cell Differentiation; Cell Line, Tumor; Cell Lineage; Cytokines; Digoxin; Encephalomyelitis, Autoimmune, Experimental; Gene Regulatory Networks; Heterocyclic Compounds, 4 or More Rings; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Nuclear Receptor Subfamily 1, Group F, Member 3; Peptide Fragments; Protein Binding; Structure-Activity Relationship; Systems Biology; T-Lymphocyte Subsets; Th17 Cells; Transcription, Genetic; Transcriptional Activation