title: CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case-control study.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls.
  
  
  METHODS
  Peripheral blood CD4 T cells were isolated from 53 RA patients with active disease and 45 healthy individuals; 13 cases and 10 controls were enrolled in microarray analysis. The remaining 40 cases and 35 controls were recruited as an independent cohort for the validation study. Bioinformatics was performed on Gene Ontology (GO), gene-gene interaction networks, and pathway analysis. The gene modules, by combining the results from GO, gene networks, and pathway analysis, were selected for further validation.
  
  
  RESULTS
  The CD4 T cells showed 1,496 differentially expressed (DE) genes in RA patients relative to healthy individuals. GO analysis revealed that the DE genes were enriched in immune response, T-cell response, apoptosis process, and Wnt receptor signaling. Pathway analysis also identified that 'Wnt signaling pathway' was differentially regulated between two groups (P=2.78×10(-10)). By gene-gene network analysis, we found that the DE genes were enriched in T-cell receptor (TCR), JAK-STAT signaling, and Wnt signaling pathway. By gene module analysis, we found that a number of DE genes overlapped in the three different analyses. In total, 23 genes were selected for further validation, and nine genes were confirmed. Of these, four genes (SOCS3, CBL, IFNAR1, and PIK3CA) were involved in STAT3 (signal transducer and activator of transcription 3) signaling, and three genes (CBL, KLF9, and CSNK2A1) were involved in the Wnt signaling pathway. Additionally, several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) were confirmed.
  
  
  CONCLUSIONS
  We report here the first case-control study of the CD4 T-cell transcriptome profile in RA. Our data provide evidence that CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Our results also suggest that the aberrant expression of several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) may be potential pathogenic factors for RA.
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. yehbmu@yahoo.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. zhangjing1002@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Mathematical Sciences, Center for Quantitative Biology, Peking University, 136 North Zhong-guan-cun Street, Beijing, 100871, China. junwangcqb@pku.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. gaoyanyan_123@yeah.net.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. sdtaduyan1115@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. fiona_leechun@163.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Mathematical Sciences, Center for Quantitative Biology, Peking University, 136 North Zhong-guan-cun Street, Beijing, 100871, China. dengmh@pku.edu.cn.
authors.forename: Minghua
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. jpguo99@gmail.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, China. li99@bjmu.edu.cn.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D050796:STAT3 Transcription Factor; D012313:RNA