Small-Molecule ROR纬t Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms

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• 作者：Sheng Xiao¹ ; ¹² ; Nir Yosef¹ ; ² ; ¹² ; Jianfei Yang³ ; Yonghui Wang⁴ ; Ling Zhou⁴ ; Chen Zhu¹ ; Chuan Wu¹ ; Erkan Baloglu³ ; Darby Schmidt³ ; Radha Ramesh³ ; Mercedes Lobera³ ; Mark S. Sundrud³ ; Pei-Yun Tsai⁵ ; Zhijun Xiang⁴ ; Jinsong Wang⁴ ; Yan Xu⁴ ; Xichen Lin⁴ ; Karsten Kretschmer⁵ ; Peter B. Rahl⁶ ; Richard A. Young⁶ ; ⁷ ; Zhong Zhong⁴ ; David A. Hafler⁸ ; Aviv Regev² ; ⁹ ; Shomir Ghosh³ ; Alexander Marson¹⁰ ; ¹¹ ; ^{alexander.marson@ucsf.edu" class="auth_mail} ; Vijay K. Kuchroo¹ ; ^{vkuchroo@rics.bwh.harvard.edu" class="auth_mail}
• 刊名：Immunity
• 出版年：17 April, 2014
• 年：2014
• 卷：40
• 期：4
• 页码：477-489
• 全文大小：4402 K

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Summary

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