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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.* ; Young, R.A.* ; Zhong, Z.* ; Hafler, D.A.* ; Regev, A.* ; Ghosh, S.* ; Marson, A.* ; Kuchroo, V.K.*

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

Immunity 40, 477-489 (2014)
DOI Verlagsversion bestellen
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Zeitschrift Immunity
Quellenangaben Band: 40, Heft: 4, Seiten: 477-489 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)