RORγt and RORα signature genes in human Th17 cells

RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its t...

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Published in:PloS one Vol. 12; no. 8; p. e0181868
Main Authors: Castro, Glenda, Liu, Xuejun, Ngo, Karen, De Leon-Tabaldo, Aimee, Zhao, Shanrong, Luna-Roman, Rosa, Yu, Jingxue, Cao, Tinghua, Kuhn, Robert, Wilkinson, Patrick, Herman, Krystal, Nelen, Marina I., Blevitt, Jonathan, Xue, Xiaohua, Fourie, Anne, Fung-Leung, Wai-Ping
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.08.2017
Public Library of Science (PLoS)
Subjects:
Arthritis
Autoimmune diseases
Biology and life sciences
Biomarkers
Biomarkers - metabolism
CCL20 protein
CCR6 protein
CD4 antigen
Cell Differentiation
Clinical trials
Cytokines
Differentiation (biology)
Gene expression
Gene Expression Profiling
Gene Expression Regulation
Gene sequencing
Genes
Genes, Reporter
Helper cells
Humans
Inhibitory Concentration 50
Leukocytes, Mononuclear - cytology
Ligands
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Medical research
Medicine and Health Sciences
Modulators
Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism
Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
Patients
Pharmacodynamics
Pharmacology
Psoriasis
Recombinant Proteins - metabolism
Research and analysis methods
Ribonucleic acid
RNA
RNA, Small Interfering - metabolism
siRNA
Skin diseases
Th1 Cells - cytology
Th17 Cells - metabolism
Transcription factors
United States > US
California
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary:RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα as well albeit a weaker influence. Key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 were shown to be regulated by both RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORα could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate RORγt or RORα activities in patients.
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Competing Interests: All authors are employees of Janssen R&D. The RORgt inverse agonists were generated by Janssen R&D and will require material transfer agreements prior to sharing but this does not alter our adherence to PLOS ONE policies on sharing data and materials.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0181868