title: FRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells.
abstract: Signal transducers and activators of transcription 5(STAT5) are cytokine induced signaling proteins, which regulate key immunological processes, such as tolerance induction, maintenance of homeostasis, and CD4 T-effector cell differentiation. In this study, transcriptional targets of STAT5 in CD4 T cells were studied by Chromatin Immunoprecipitation (ChIP). Genomic mapping of the sites cloned and identified in this study revealed the striking observation that the majority of STAT5-binding sites mapped to intergenic (>50 kb upstream) or intronic, rather than promoter proximal regions. Of the 105 STAT5 responsive binding sites identified, 94% contained the canonical (IFN-γ activation site) GAS motifs. A number of putative target genes identified here are associated with tumor biology. Here, we identified Fos-related antigen 2 (FRA2) as a transcriptional target of IL-2 regulated STAT5. FRA2 is a basic -leucine zipper (bZIP) motif 'Fos' family transcription factor that is part of the AP-1 transcription factor complex and is also known to play a critical role in the progression of human tumours and more recently as a determinant of T cell plasticity. The binding site mapped to an internal intron within the FRA2 gene. The epigenetic architecture of FRA2, characterizes a transcriptionally active promoter as indicated by enrichment for histone methylation marks H3K4me1, H3K4me2, H3K4me3, and transcription/elongation associated marks H2BK5me1 and H4K20me1. FRA2 is regulated by IL-2 in activated CD4 T cells. Consistently, STAT5 bound to GAS sequence in the internal intron of FRA2 and reporter gene assays confirmed IL-2 induced STAT5 binding and transcriptional activation. Furthermore, addition of JAK3 inhibitor (R333) or Daclizumab inhibited the induction in TCR stimulated cells. Taken together, our data suggest that FRA2 is a novel STAT5 target gene, regulated by IL-2 in activated CD4 T cells.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom.
authors.forename: Aradhana
authors.initials: A
authors.lastname: Rani
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom.
authors.forename: Roseanna
authors.initials: R
authors.lastname: Greenlaw
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom.
authors.forename: Manohursingh
authors.initials: M
authors.lastname: Runglall
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom.
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
authors.affiliation: Department of Immunobiology, King's College London, London, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: John
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021901:DNA, Intergenic / Q000737:chemistry / Q000378:metabolism; D000077561:Daclizumab; D044127:Epigenesis, Genetic; D051921:Fos-Related Antigen-2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007438:Introns; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008745:Methylation; D008969:Molecular Sequence Data; D061251:Primary Cell Culture; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D021901:DNA, Intergenic; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; D006657:Histones; D007074:Immunoglobulin G; D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D000077561:Daclizumab; D008156:Luciferases; C507933:JAK3 protein, human; D053616:Janus Kinase 3