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Specifically to Iga Increases Class Switch Recombination the Histone The Histone Methyltransferase Suv39h1 Increases Class Switch Recombination Specifically to IgA This information is current as Sean P. Bradley, Denise A. Kaminski, Antoine H. F. M. of September 27, 2021. Peters, Thomas Jenuwein and Janet Stavnezer J Immunol 2006; 177:1179-1188; ; doi: 10.4049/jimmunol.177.2.1179 http://www.jimmunol.org/content/177/2/1179 Downloaded from References This article cites 66 articles, 38 of which you can access for free at: http://www.jimmunol.org/content/177/2/1179.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Histone Methyltransferase Suv39h1 Increases Class Switch Recombination Specifically to IgA1 Sean P. Bradley,2* Denise A. Kaminski,* Antoine H. F. M. Peters,3† Thomas Jenuwein,† and Janet Stavnezer4* Ab class (isotype) switching allows the humoral immune system to adaptively respond to different infectious organisms. Isotype switching occurs by intrachromosomal DNA recombination between switch (S) region sequences associated with CH region genes. Although isotype-specific transcription of unrearranged (germline) CH genes is required for switching, recent results suggest that isotype specificity is also determined by the sequences of downstream (acceptor) S regions. In the current study, we identify the histone methyltransferase Suv39h1 as a novel S␣-specific factor that specifically increases IgA switching (S␮-S␣ recombination) in a transiently transfected plasmid S substrate, and demonstrate that this effect requires the histone methyltransferase activity of Suv39h1. Additionally, B cells from Suv39h1-deficient mice have an isotype-specific reduction in IgA switching with no effect Downloaded from on the level of germline I␣-C␣ transcripts. Taken together, our results suggest that Suv39h1 activity inhibits the activity of a sequence-specific DNA-binding protein that represses switch recombination to IgA. The Journal of Immunology, 2006, 177: 1179–1188. pon activation by Ag and accessory signals, naive Together with B cell activators, the cytokines IL-4, IFN-␥, and ϩ ϩ IgM IgD B cells undergo Ig class switching, resulting TGF-␤ regulate GL transcription, which in-turn regulates isotype http://www.jimmunol.org/ in expression of a different C gene, while maintaining specificity. IL-4 induces GLTs from the unrearranged C␥1 and C␧ U H expression of the same V region gene. Because the CH region genes, and directs switching to IgG1 and IgE in LPS- or CD40L- determines the Ab effector function, class switching allows opti- activated mouse splenic B cells. TGF-␤ induces ␣ and ␥2b GLTs and mization of the Ab for elimination of different pathogens. Class directs switching to IgA and to IgG2b. IFN-␥ induces GL ␥3 and ␥2a switching is mediated by DNA recombination between switch (S)5 transcripts, and directs switching to IgG3 and to IgG2a (1). Ј ␦ ␤ ␣ region sequences located 5 to each CH gene, except C . The iso- TGF- is required for induction of GLTs, but very poor type to which the B cells will S is regulated by Th cells, by the switching to IgA is induced by treatment of cells with LPS ϩ particular APCs involved, and by the anatomical site of Ag pre- TGF-␤ alone. Although a mixture of activators (LPS, or CD40L, ϩ ␦ ϩ ϩ ϩ ␤ by guest on September 27, 2021 sentation (1). Transcripts from unrearranged CH genes, termed anti-IgD ( ) dextran IL-4 IL-5 TGF- ) increases IgA germline (GL) transcripts (GLTs), are essential for regulating iso- switching in splenic B cells, the frequencies are still quite low type specificity of class switch recombination (CSR) (2, 3). Recent compared with most isotypes (11). The poor switching in culture evidence indicates that one function of GL transcription is to create is especially puzzling because IgA is the most abundant isotype in a transcription bubble and an R-loop, resulting in S region ssDNA the body, although mostly limited to mucosal areas (12). This re- (4). ssDNA is the substrate for activation-induced deaminase stricted expression suggests that something special in the mucosal (AID), the enzyme that initiates CSR by deamination of dC resi- environment supports IgA switching and expression. dues within S regions (5–10). Additional regulation of CSR isotype specificity *Immunology and Virology Program, Department of Molecular Genetics and Micro- A plasmid assay for switch recombination (SR) has been devel- biology, University of Massachusetts Medical School, Worcester, MA 01655; and oped to examine the regulation of isotype specificity (13, 14). In † Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria this assay, plasmids containing both the S␮ segment and a down- Received for publication March 24, 2006. Accepted for publication May 1, 2006. stream S region segment are transiently transfected into B cell The costs of publication of this article were defrayed in part by the payment of page lines or splenic B cells. Such plasmid substrates undergo AID- charges. This article must therefore be hereby marked advertisement in accordance ␮ with 18 U.S.C. Section 1734 solely to indicate this fact. dependent S -Sx recombination in B cells capable of undergoing CSR, but not in cell types that do not undergo CSR (14, 15). 1 This work was supported by grants from the National Institutes of Health: R01 AI 23283 and R21 AI 57463 (to J.S.) and F32 AI 56806 (to D.A.K.). Importantly, these plasmids show isotype specificity. The tran- ␮ ␣ 2 Current address: Department of Surgery, University of Massachusetts Medical siently transfected plasmid p273 containing S and S segments School, Worcester, MA 01655. undergoes S␮-S␣ recombination in LPS-activated splenic B cells 3 Current address: Friedrich Miescher Institute for Biomedical Research, Novartis and in three B cell lines (I.29␮, CH12.LX, and 1B4.B6) capable of Research Foundation, CH-4058 Basel, Switzerland. undergoing CSR to IgA on their endogenous chromosomes. The 4 Address correspondence and reprint requests to Dr. Janet Stavnezer, Immunology pG3.1 plasmid, in which the S␥3 segment is substituted for the S␣ and Virology Program, Department of Molecular Genetics and Microbiology, Uni- ␮ ␥ versity of Massachusetts Medical School, Worcester, MA 01655. E-mail address: segment, also undergoes S -S 3 recombination in LPS-activated [email protected] splenic B cells, but only recombines in one (1B4.B6) of the three 5 Abbreviations used in this paper: S, switch; AID, activation-induced deaminase; B cell lines, the only one that is capable of switching to IgG3 on CSR, class switch recombination; DC-PCR, digestion-circularization PCR; GL, germ- its endogenous chromosome. Additional results obtained using line; GLT, GL transcript; HMT, histone methyltransferase; HP-1, heterochromatin protein-1; LSF, late SV40 factor; me3, trimethyl; Sbf-1, SET-binding factor-1; SR, S other plasmids that differ only in the downstream acceptor S region recombination; WT, wild type. provided evidence for factors that discriminate between the S␣, Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 1180 Suv39h1 IS AN IgA-SPECIFIC SWITCH FACTOR S␥3, S␥1, and S␧ segments (16). These data have led to the hy- K9-H3 and HP-1␥ are associated with transcribed segments of pothesis that, in addition to GLTs, differentially expressed factors active genes in an erythroid cell line and in primary T cells (44). bind different acceptor S regions and regulate isotype-specific CSR The specific HMT that performs this modification at actively tran- by regulating chromatin accessibility. It has also been suggested scribed genes is unknown. Thus, although me3-K9-H3 is generally that such factors might directly bind AID to recruit it to specific an inhibitory modification, it is possible that very low levels of this downstream S regions (15). modification, perhaps if combined with certain additional modifi- cations, can be activating. Histone modification and Suv39h1 In this study, we investigate whether Suv39h1 has an effect on Enzymatic modification of histones can either increase or decrease CSR. We find that overexpression of Suv39h1 increases SR spe- chromatin accessibility to transcription, DNA repair, and recom- cifically to the S␣ segment in a transiently transfected plasmid, and bination machinery. Acetylation of the N-terminal tails of histone that this enhancement requires the HMT activity of Suv39h1. Fur- H3 or H4 generally correlates with an increase in chromatin ac- thermore, B cells from mice deficient in Suv39h1 or both Suv39h1 cessibility. Methylation of H3 or H4 N-terminal tails inhibits or and Suv39h2 have a reduced ability to switch to IgA, with no effect increases gene activity, depending on the specific amino acid res- on the levels of ␣ GLTs. We suggest possible models for how idue that is methylated and the level of methylation (17–19). Sev- Suv39h1 specifically stimulates IgA CSR. eral R and K residues within the H3 and H4 N-terminal tails can be acetylated or methylated, singly or in combination, determined Materials and Methods by the specificity of the enzymes involved. In addition, some K S plasmid construction residues can be ubiquitinated, and some S residues can be phos- Downloaded from S plasmids p273, p218, pG3.1, and pE.1 were previously described (13, phorylated, but very little is known about the roles of these latter 16).
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