Chemical Inhibition of the ROR?t-dependent Transcriptional Network in Th17 cells [RNA-Seq]

ROR?t is a transcription factor required for T helper 17 (Th17) cell development. We identified three ROR?t-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized ROR?t binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and ROR?t-deficient cells. ROR?t is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced ROR?t from its target-loci, the two more potent 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. Overall design: Transcriptional profiling of Th17 cells under chemical perturbations of ROR?t, DMSO, and knockout of ROR?t

7

Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C, Wu C, Baloglu E, Schmidt D, Ramesh R, Lobera M, Sundrud MS, Tsai PY, Xiang Z, Wang J, Xu Y, Lin X, Kretschmer K, Rahl PB, Young RA, Zhong Z, Hafler DA, Regev A, Ghosh S, Marson A, Kuchroo VK