Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/110329 https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826206238428364800 |
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| author | Xiao, Sheng Yosef, Nir Yang, Jianfei Wang, Yonghui Zhou, Ling Zhu, Chen Wu, Chuan Baloglu, Erkan Schmidt, Darby Ramesh, Radha Lobera, Mercedes Sundrud, Mark S. Tsai, Pei-Yun Xiang, Zhijun Wang, Jinsong Xu, Yan Lin, Xichen Kretschmer, Karsten Rahl, Peter B. Zhong, Zhong Hafler, David A. Ghosh, Shomir Marson, Alexander Kuchroo, Vijay K. Regev, Aviv Young, Richard A. |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Xiao, Sheng Yosef, Nir Yang, Jianfei Wang, Yonghui Zhou, Ling Zhu, Chen Wu, Chuan Baloglu, Erkan Schmidt, Darby Ramesh, Radha Lobera, Mercedes Sundrud, Mark S. Tsai, Pei-Yun Xiang, Zhijun Wang, Jinsong Xu, Yan Lin, Xichen Kretschmer, Karsten Rahl, Peter B. Zhong, Zhong Hafler, David A. Ghosh, Shomir Marson, Alexander Kuchroo, Vijay K. Regev, Aviv Young, Richard A. |
| author_sort | Xiao, Sheng |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:26:17Z |
| format | Article |
| id | mit-1721.1/110329 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:26:17Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1103292022-10-01T15:19:00Z Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms Xiao, Sheng Yosef, Nir Yang, Jianfei Wang, Yonghui Zhou, Ling Zhu, Chen Wu, Chuan Baloglu, Erkan Schmidt, Darby Ramesh, Radha Lobera, Mercedes Sundrud, Mark S. Tsai, Pei-Yun Xiang, Zhijun Wang, Jinsong Xu, Yan Lin, Xichen Kretschmer, Karsten Rahl, Peter B. Zhong, Zhong Hafler, David A. Ghosh, Shomir Marson, Alexander Kuchroo, Vijay K. Regev, Aviv Young, Richard A. Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Biology Regev, Aviv Young, Richard A 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. United States. National Institutes of Health (DP1OD003958-01) 2017-06-27T18:55:05Z 2017-06-27T18:55:05Z 2014-04 2012-12 Article http://purl.org/eprint/type/JournalArticle 1074-7613 1097-4180 http://hdl.handle.net/1721.1/110329 Xiao, Sheng; Yosef, Nir; Yang, Jianfei; Wang, Yonghui; Zhou, Ling; Zhu, Chen; Wu, Chuan; Baloglu, Erkan et al. "Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms." Immunity 40, 4 (April 2014): 477–489 © 2014 Elsevier Inc https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1016/j.immuni.2014.04.004 Immunity Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Xiao, Sheng Yosef, Nir Yang, Jianfei Wang, Yonghui Zhou, Ling Zhu, Chen Wu, Chuan Baloglu, Erkan Schmidt, Darby Ramesh, Radha Lobera, Mercedes Sundrud, Mark S. Tsai, Pei-Yun Xiang, Zhijun Wang, Jinsong Xu, Yan Lin, Xichen Kretschmer, Karsten Rahl, Peter B. Zhong, Zhong Hafler, David A. Ghosh, Shomir Marson, Alexander Kuchroo, Vijay K. Regev, Aviv Young, Richard A. Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title | Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title_full | Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title_fullStr | Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title_full_unstemmed | Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title_short | Small-Molecule RORγt Antagonists Inhibit T Helper 17 Cell Transcriptional Network by Divergent Mechanisms |
| title_sort | small molecule rorγt antagonists inhibit t helper 17 cell transcriptional network by divergent mechanisms |
| url | http://hdl.handle.net/1721.1/110329 https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0001-8855-8647 |
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