Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2015-05, Vol.42 (5), p.877-889

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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. [Display omitted] •The transcriptomic output driven by IL-6 or IL-27 is primarily regulated by STAT3•STAT1 does not compensate for STAT3 to drive transcriptional output•Much of STAT1 binding to chromatin is STAT3-dependent•The ability to access STAT1 magnifies the difference between IL-6 and IL-27 Interleukin-6 (IL-6) and IL-27 are ascribed unique and overlapping functions while sharing a receptor subunit and downstream STAT. Using genomic approaches, O’Shea and colleagues report that STAT3 is responsible for transcriptomic output, whereas STAT1 regulates cytokine specificity.