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Immunity DOI:10.1016/j.immuni.2014.04.004

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

Publication TypeJournal Article
Year of Publication2014
AuthorsXiao, 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
JournalImmunity
Volume40
Issue4
Pages477-89
Date Published2014 Apr 17
ISSN1097-4180
KeywordsAndrostenols, Animals, Benzeneacetamides, Benzhydryl Compounds, Cell Differentiation, Cell Line, Tumor, Cell Lineage, Cytokines, Digoxin, Encephalomyelitis, Autoimmune, Experimental, Gene Regulatory Networks, Heterocyclic Compounds, 4 or More Rings, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiple Sclerosis, Myelin-Oligodendrocyte Glycoprotein, Nuclear Receptor Subfamily 1, Group F, Member 3, Peptide Fragments, Protein Binding, Structure-Activity Relationship, Systems Biology, T-Lymphocyte Subsets, Th17 Cells, Transcription, Genetic, Transcriptional Activation
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1074-7613(14)00118-6
DOI10.1016/j.immuni.2014.04.004
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24745332?dopt=Abstract

Alternate JournalImmunity
PubMed ID24745332
PubMed Central IDPMC4066874
Grant ListR01 NS030843 / NS / NINDS NIH HHS / United States
K01 DK090105 / DK / NIDDK NIH HHS / United States
K01DK090105 / DK / NIDDK NIH HHS / United States
DP1OD003958-01 / OD / NIH HHS / United States
P01 NS076410 / NS / NINDS NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U01 AI102011 / AI / NIAID NIH HHS / United States
R01NS030843, / NS / NINDS NIH HHS / United States
P01NS076410, / NS / NINDS NIH HHS / United States
P01AI039671 / AI / NIAID NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States