Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity

Kiyoshi Hirahara, Atsushi Onodera, Alejandro V. Villarino, Michael Bonelli, Giuseppe Sciumè, Arian Laurence, Hong Wei Sun, Stephen R. Brooks, Golnaz Vahedi, Han Yu Shih, Gustavo Gutierrez-Cruz, Shigeru Iwata, Ryo Suzuki, Yohei Mikami, Yoshitaka Okamoto, Toshinori Nakayama, Steven M. Holland, Christopher A. Hunter, Yuka Kanno, John J. O'Shea

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)


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 chromatin immunoprecipitation-sequencing (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 Tcells 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.

Original languageEnglish
Pages (from-to)877-889
Number of pages13
Issue number5
Publication statusPublished - 2015 May 19
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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