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345.Full.Pdf Brahma-Related Gene 1-Dependent STAT3 Recruitment at IL-6-Inducible Genes Zuyao Ni and Rod Bremner This information is current as J Immunol 2007; 178:345-351; ; of October 1, 2021. doi: 10.4049/jimmunol.178.1.345 http://www.jimmunol.org/content/178/1/345 References This article cites 41 articles, 18 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/178/1/345.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 1, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Brahma-Related Gene 1-Dependent STAT3 Recruitment at IL-6-Inducible Genes1 Zuyao Ni and Rod Bremner2 IL-6 is an immunoregulatory cytokine with multiple functions in hemopoiesis, proliferation, and tumorigenesis. IL-6 triggers phosphorylation, dimerization, and nuclear translocation of STAT3, which binds to target promoters and activates transcription. Brahma-related gene 1 (BRG1), the enzymatic engine of the yeast-mating type-switching and sucrose-nonfermenting chromatin- remodeling complex, is essential for recruitment of STAT1 or STAT1/STAT2-containing complexes to IFN targets. We hypoth- esized that BRG1 might also be required for STAT3 recruitment. In this study, we show that induction of a subset of human IL-6-responsive genes is BRG1 dependent. BRG1 is constitutively present at these targets and is required for STAT3 recruitment, downstream histone modifications, and IL-6-induced chromatin remodeling. IL-6-induced recruitment of STAT3 to the IFN regulatory factor 1 promoter and subsequent mRNA synthesis is BRG1 dependent, even though IFN-␥-mediated STAT1 recruit- ment to this locus is BRG1 independent. BRG1 also increased basal expression of IFN-induced transmembrane protein 3 and Downloaded from IFN-␥-induced protein 16, and the basal chromatin accessibility at the promoter of IFN regulatory factor 1. The effect on basal expression was STAT3 independent, as revealed by small interfering RNA knockdown. Together with prior observations, these data reveal that BRG1 has a broad role in mediating STAT accessibility at multiple cytokine-responsive promoters and exposes promoter specific differences in both the effect of BRG1 on basal chromatin accessibility and on access of different STAT proteins to the same target. The Journal of Immunology, 2007, 178: 345–351. http://www.jimmunol.org/ hromatin remodeling is fundamental to gene regulation quently others reported that it is also essential for induction of a in eukaryotes and is mediated by two categories of en- subset of IFN-␣-responsive targets (8, 9). Moreover, the BAF47 C zymes that either use the energy of ATP hydrolysis to and BAF200 components of SWI/SNF are also required for IFN alter nucleosome structure or position, or that covalently modify signaling, although the INI1 and BAF180 proteins are dispensable histones (1). Yeast mating type switching and sucrose nonferment- (10–12). These findings highlight an important role for SWI/SNF ing (SWI/SNF)3 is one complex that uses ATP hydrolysis to reg- in the immune response. ulate the position and structure of nucleosomes, which can lead to In view of the findings that BRG1 binds STAT2 and STAT3 (8, either gene activation or repression (2). There are more than 10 13) and that SWI/SNF typically functions downstream of primary by guest on October 1, 2021 components of SWI/SNF (3) which can interact with a variety of activators in gene induction cascades (14–21), it seemed logical activators or repressors (2). that BRG1 might act after STAT1 recruitment at IFN targets. In- Brahma-related gene 1 (BRG1) is the ATPase subunit of SWI/ stead, BRG1 is essential for STAT1 recruitment at multiple IFN-␣ SNF and has been linked to differentiation, proliferation, and tu- and IFN-␥ targets (22). In contrast, constitutive BRG1 recruitment morigenesis. Homozygous inactivation of BRG1 causes early em- is STAT1 independent (22). All of the subsequent IFN-induced bryonic lethality in mice and heterozygotes are prone to a variety events, including chromatin remodeling, histone modifications, of tumors (4–6). Previously, we showed that BRG1 is required for and transcription are blocked if BRG1 is absent (10, 22). Thus, induction of a subset of IFN-␥-responsive genes (7) and subse- BRG1 has an apical role in IFN signaling. IL-6 is an important immunoregulatory cytokine with multiple functions in hemopoietic proliferation, differentiation of B cells, Toronto Western Research Institute, University Health Network, Department of Oph- and tumorigenesis. For example, it is essential for the growth and thalmology and Vision Science, Vision Science Research Program, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada survival of B lymphocyte-derived murine plasmacytomas and hu- man myelomas, and, most likely, IL-6 promotes such tumors by Received for publication June 13, 2006. Accepted for publication October 24, 2006. increasing proliferation and inhibiting apoptosis (23, 24). IL-6 trig- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance gers tyrosine phosphorylation and activation of JAKs. Activated with 18 U.S.C. Section 1734 solely to indicate this fact. JAKs phosphorylate STAT3 which forms either a homodimer or a 1 This work was supported by the National Cancer Institute of Canada with funds STAT3/1 heterodimer, which translocates to the nucleus and bind from the Canadian Cancer Society. Z.N. was supported by fellowships from Ontario to the STAT-binding site at target loci (25). Graduate studentships, the Vision Science Research Program, the Frank Fletcher Me- morial Fund, and the Dr. R. Dittakavi and Dr. P. Rao Graduate Award. A direct link between IL-6 signaling and BRG1 has never been waf1 2 Address correspondence and reprint requests to Dr. Rod Bremner, Toronto Western established. However, BRG1 associates with STAT3 at the p21 Research Institute, MC6-424, Cellular and Molecular Division, 399 Bathurst Street, promoter (13), raising the possibility that, in addition to IFN tar- Toronto, Ontario, Canada M5T 2S8. E-mail address: [email protected] gets, BRG1 may have a broader role in cytokine signaling. In this 3 Abbreviations used in this paper: SWI/SNF, yeast mating type switching and su- study, we provide in vivo evidence that BRG1 is required for IL- crose nonfermenting; IRF1, IFN regulatory factor 1; qPCR, quantitative real-time PCR; IFI16, IFN-␥-inducible protein 16; ChIP, chromatin immunoprecipitation; IP, 6-induced expression at a subset of target genes. As seen at IFN immunoprecipitated; RSB, reticulocyte standard buffer; siRNA, small interfering targets (22), BRG1 constitutively binds to IL-6-responsive promot- RNA; IFITM3, IFN-induced transmembrane protein 3; MNDA, myeloid cell nuclear ers and is essential for all events, including IL-6-induced STAT3 differentiation Ag. recruitment, chromatin remodeling, and covalent histone modifi- Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$2.00 cations. Intriguingly, BRG1 has promoter-specific effects on basal www.jimmunol.org 346 BRG1-DEPENDENT STAT3 RECRUITMENT Table I. List of primers Gene Region Forward (5Ј to 3Ј) Reverse (5Ј to 3Ј) IFI16 Promoter CATGTTGAGAGTCCACTATCCACG CACTAGCTGTCCTCTTGACCATGA Promoter (DNase I assay) ACCCATTAAAGTAATTTCTCATCCC CCAGTGTTTTTAGCTTTCGTTTCT Exon 9 ATGGTGCTGAACGCAACAGA CCTTCACTCGGAAGACTTCATTC IRF1 Promoter GCTAAGTGTTTGGATTGCTCGGTGG TTGCCTCGACTAAGGAGTGGCGAGC Promoter (DNase I assay) CGCCCGGCCGGAGAGGGTGGG CCGCGCGGGCGCCCATTGGC Last exon AGGCCATTCCCTGTGCACCGTAGCA GTCCAGCTTCTCTGCACCATATCCA ISGF3G Promoter ATGGGATCTCTGGGACCTGTT AACTGACACTTTGGGAGGGAAC Last exon TACGCCCTCTTTCATCTGTAAGG GGAGGTCAGGGAAGAGGGAA MNDA Promoter TGCTCCTGCCACTCTGTGAA GGTAGCCGCTTGAATAAGGATCTT Exon 6 AACTTCGACTCTTCTGCCTTCAA GCTGTGACTTCCACACACCAGT AIM2 Promoter AGTTCCTATGTGGCATGACTCAGA GGGTTCTCACTAGCAGCCACAG Last exon GCCAACTGGTCTAAGCAGCAT GGAGCCTGTGAACTGCAGCT CIITA Exon 20 ACGTCTGACAGGCAATGCTG GGGTCCTAGCCAACTATTCCG IFI27 Last exon TCTCCGGATTGACCAAGTTCA CAGGGAGCTAGTAGAACCTCGC GBP1 Last exon CCAGATGACCAGCAGTAGACAAAT GCCAGACCAATGCCCAAATAT IFITM3 Promoter ATTTGTTCCGCCCTCATCTG GTTTCGGTTTCTCAACAGTTTCCT Last exon CCATTCTGCTCATCGTCATCC AGAGCTCCTGGCCTCAGTGA IFIT1 Last exon AAGGCAGGCTGTCCGCTTA TCCTGTCCTTCATCCTGAAGCT 6-16 (GIP3) Last exon CAGCAGCGTCGTCATAGGTAAT TCCTCATCCTCCTCACTATCGAG Downloaded from p21Waf1 Last exon GTGACAATAACAAAGGCTGGCC CTGACAGGACACTTCTGTTGTTGA Cyclin D1 Last exon GTTGACTTCCAGGCACGGTT GATCCTCCAATAGCAGCAAACAAT UCK 2 Last exon GGAGGCACTGCTCATCTGTACA TCAAAGGCATTTCATCTCCATG JunB Last exon CCAGCTCAAACAGAAGGTCATG GACGTTCAGAAGGCGTGTCC Bcl-xL Last exon CTGGGTTCCCTTTCCTTCCA TCCCAAGCAGCCTGAATCC
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