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 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.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Yang
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Darby
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramesh
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lobera
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Pei-Yun
authors.initials: PY
authors.lastname: Tsai
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Xichen
authors.initials: X
authors.lastname: Lin
authors.affiliation: Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kretschmer
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Rahl
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: Tempero Pharmaceuticals (a GlaxoSmithKline company), Cambridge, MA 02139, USA.
authors.forename: Shomir
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: alexander.marson@ucsf.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marson
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: vkuchroo@rics.bwh.harvard.edu.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000737:Androstenols / Q000737:chemistry; D000818:Animals; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004077:Digoxin / Q000737:chemistry / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D049490:Systems Biology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000737:Androstenols; D044482:Benzeneacetamides; D001559:Benzhydryl Compounds; D016207:Cytokines; D006576:Heterocyclic Compounds, 4 or More Rings; D063308:Myelin-Oligodendrocyte Glycoprotein; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010446:Peptide Fragments; C588348:TMP778; C000589554:TMP920; C517781:myelin oligodendrocyte glycoprotein (34-56); C017039:azastene; D004077:Digoxin
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