Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms

Sheng Xiao; Nir Yosef; Jianfei Yang; Yonghui Wang; Ling Zhou; Chen Zhu; Chuan Wu; Erkan Baloglu; Darby Schmidt; Radha Ramesh; Mercedes Lobera; Mark S. Sundrud; Pei-Yun Tsai; Zhijun Xiang; Jinsong Wang; Yan Xu; Xichen Lin; Karsten Kretschmer; Peter B. Rahl; Richard A. Young; Zhong Zhong; David A. Hafler; Aviv Regev; Shomir Ghosh; Alexander Marson; Vijay K. Kuchroo

doi:https://doi.org/10.1016/j.immuni.2014.04.004

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms

Sheng Xiao, Nir Yosef, Jianfei Yang, Yonghui Wang, Ling Zhou, Chen Zhu, Chuan Wu, Erkan Baloglu, Darby Schmidt, Radha Ramesh, Mercedes Lobera, Mark S. Sundrud, Pei-Yun Tsai, Zhijun Xiang, Jinsong Wang, Yan Xu, Xichen Lin, Karsten Kretschmer, Peter B. Rahl, Richard A. YoungZhong Zhong, David A. Hafler, Aviv Regev, Shomir Ghosh, Alexander Marson, Vijay K. Kuchroo

Research output: Contribution to journal › Article › peer-review

Abstract

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 Tcell 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 Tcell 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.

Original language	English
Pages (from-to)	477-489
Number of pages	13
Journal	Immunity
Volume	40
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2014.04.004
State	Published - 17 Apr 2014
Externally published	Yes

All Science Journal Classification (ASJC) codes

Infectious Diseases
Immunology and Allergy
Immunology

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Xiao, S., Yosef, N., Yang, J., Wang, Y., Zhou, L., Zhu, C., Wu, C., Baloglu, E., Schmidt, D., Ramesh, R., Lobera, M., Sundrud, M. S., Tsai, P-Y., Xiang, Z., Wang, J., Xu, Y., Lin, X., Kretschmer, K., Rahl, P. B., ... Kuchroo, V. K. (2014). Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity, 40(4), 477-489. https://doi.org/10.1016/j.immuni.2014.04.004

@article{4dbe333025914ca28a8edcba68b02431,

title = "Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms",

abstract = "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 Tcell 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 Tcell 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.",

author = "Sheng Xiao and Nir Yosef and Jianfei Yang and Yonghui Wang and Ling Zhou and Chen Zhu and Chuan Wu and Erkan Baloglu and Darby Schmidt and Radha Ramesh and Mercedes Lobera and Sundrud, {Mark S.} and Pei-Yun Tsai and Zhijun Xiang and Jinsong Wang and Yan Xu and Xichen Lin and Karsten Kretschmer and Rahl, {Peter B.} and Young, {Richard A.} and Zhong Zhong and Hafler, {David A.} and Aviv Regev and Shomir Ghosh and Alexander Marson and Kuchroo, {Vijay K.}",

year = "2014",

month = apr,

day = "17",

doi = "https://doi.org/10.1016/j.immuni.2014.04.004",

language = "الإنجليزيّة",

volume = "40",

pages = "477--489",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "4",

}

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, P-Y, 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 2014, 'Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms', Immunity, vol. 40, no. 4, pp. 477-489. https://doi.org/10.1016/j.immuni.2014.04.004

TY - JOUR

T1 - Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms

AU - Xiao, Sheng

AU - Yosef, Nir

AU - Yang, Jianfei

AU - Wang, Yonghui

AU - Zhou, Ling

AU - Zhu, Chen

AU - Wu, Chuan

AU - Baloglu, Erkan

AU - Schmidt, Darby

AU - Ramesh, Radha

AU - Lobera, Mercedes

AU - Sundrud, Mark S.

AU - Tsai, Pei-Yun

AU - Xiang, Zhijun

AU - Wang, Jinsong

AU - Xu, Yan

AU - Lin, Xichen

AU - Kretschmer, Karsten

AU - Rahl, Peter B.

AU - Young, Richard A.

AU - Zhong, Zhong

AU - Hafler, David A.

AU - Regev, Aviv

AU - Ghosh, Shomir

AU - Marson, Alexander

AU - Kuchroo, Vijay K.

PY - 2014/4/17

Y1 - 2014/4/17

N2 - 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 Tcell 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 Tcell 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.

AB - 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 Tcell 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 Tcell 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.

UR - http://www.scopus.com/inward/record.url?scp=84898688169&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.immuni.2014.04.004

DO - https://doi.org/10.1016/j.immuni.2014.04.004

M3 - مقالة

C2 - 24745332

SN - 1074-7613

VL - 40

SP - 477

EP - 489

JO - Immunity

JF - Immunity

IS - 4

ER -

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms

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