TY - JOUR
T1 - Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity
AU - Hirahara, Kiyoshi
AU - Onodera, Atsushi
AU - Villarino, Alejandro V.
AU - Bonelli, Michael
AU - Sciumè, Giuseppe
AU - Laurence, Arian
AU - Sun, Hong Wei
AU - Brooks, Stephen R.
AU - Vahedi, Golnaz
AU - Shih, Han Yu
AU - Gutierrez-Cruz, Gustavo
AU - Iwata, Shigeru
AU - Suzuki, Ryo
AU - Mikami, Yohei
AU - Okamoto, Yoshitaka
AU - Nakayama, Toshinori
AU - Holland, Steven M.
AU - Hunter, Christopher A.
AU - Kanno, Yuka
AU - O'Shea, John J.
N1 - Funding Information:
We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS), and the NIAMS LACU staff for their excellent technical support. This study utilized the high-performance computational capabilities of the Helix Systems at the NIH. This work was supported by the Intramural Research Programs of NIAMS, grant from the Ministry of Education, Culture, Sports, Science and Technology (Japan; Grants-in-Aid for Research Activity start-up #25893032), The Astellas Foundation for Research on Metabolic Disorders, The Uehara Memorial Foundation, Osaka Foundation for Promotion of Fundamental Medical Research, Kanae Foundation for the Promotion of Medical Science, and Takeda Science Foundation (K.H.).
Publisher Copyright:
© 2015 Elsevier Inc..
PY - 2015/5/19
Y1 - 2015/5/19
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2015.04.014
DO - 10.1016/j.immuni.2015.04.014
M3 - Article
C2 - 25992861
AN - SCOPUS:84929665405
SN - 1074-7613
VL - 42
SP - 877
EP - 889
JO - Immunity
JF - Immunity
IS - 5
ER -
