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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [ChIP-Seq]

ABSTRACT: RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt 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 RORγt 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. DNA binding of RORγt in WT Th17 cells and under chemical perturbations of RORγt; Additional data is included for epitope-tagged exogenous RORγt in EL4 cells (a murine lymphoma cell line)

ORGANISM(S): Mus musculus  

SUBMITTER: D A Hafler   Y Wang  Nir Yosef  J Yang  A Regev  K Kretschmer  C Zhu  J Wang  X Lin  S Ghosh  L Zhou  R Ramesh  V K Kuchroo  N Yosef  D Schmidt  S Xiao  Z Zhong  Y Xu  E Baloglu  P B Rahl  R A Young  M Lobera  A Marson  Z Xiang  P Tsai  M S Sundrud 

PROVIDER: E-GEOD-56019 | ArrayExpress | 2014-04-17



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