FRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells

Rani, A., Greenlaw, R., Runglall, M., Jurcevic, S. and John, S. 2014. FRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells. PLoS ONE. 9 (2), p. e90370. doi:10.1371/journal.pone.0090370

TitleFRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells
AuthorsRani, A., Greenlaw, R., Runglall, M., Jurcevic, S. and John, S.
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.

KeywordsSequence motif analysis, gene targeting, T helper cells, gene regulation, introns, T cells, DNA transcription, T cell receptors
JournalPLoS ONE
Journal citation9 (2), p. e90370
Year2014
Publisher's version
Digital Object Identifier (DOI)doi:10.1371/journal.pone.0090370
Web address (URL)http://dx.doi.org/10.1371/journal.pone.0090370

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