Asymmetric action of STATs drive transcriptional outputs and cytokine specificity.

2014 Fiscal Year Final Research Report

• Project/Area Number: 25893032
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Chiba University
• Principal Investigator: KIYOSHI Hirahara 千葉大学, 医学(系)研究科(研究院), 客員准教授 (00707193)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Keywords: 免疫学 / 遺伝子 / シグナル伝達 / サイトカイン

Outline of Final Research Achievements

Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins,but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and ChIP-seq approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.

Free Research Field

医歯薬学