title: Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity.
abstract: 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.
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA; Department of Advanced Allergology of the Airway, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hirahara
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Onodera
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alejandro V
authors.initials: AV
authors.lastname: Villarino
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonelli
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciumè
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
authors.affiliation: Biodata Mining and Discovery Section, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.affiliation: Biodata Mining and Discovery Section, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Brooks
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Shih
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gutierrez-Cruz
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Laboratory of Molecular Immunogenetics, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.affiliation: Department of Otorhinolaryngology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Chiba, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: The Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kannoy@mail.nih.gov.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: osheaj@arb.niams.nih.gov.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009154:Mutation; D050791:STAT Transcription Factors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002843:Chromatin; D016207:Cytokines; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor