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Enhancer, Hs3 Igh ′ Activator of the Murine 3 Yin Yang 1 Is A Yin Yang 1 Is a Lipopolysaccharide-Inducible Activator of the Murine 3 ′ Igh Enhancer, hs3 This information is current as Steven J. Gordon, Shireen Saleque and Barbara K. Birshtein of September 23, 2021. J Immunol 2003; 170:5549-5557; ; doi: 10.4049/jimmunol.170.11.5549 http://www.jimmunol.org/content/170/11/5549 Downloaded from References This article cites 66 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/170/11/5549.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 23, 2021 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Yin Yang 1 Is a Lipopolysaccharide-Inducible Activator of the Murine 3؅ Igh Enhancer, hs31 Steven J. Gordon, Shireen Saleque,2 and Barbara K. Birshtein3 The 3؅ Igh enhancers, DNase I hypersensitive site (hs) 3B and/or hs4, are required for germline transcription, and hence, class switch recombination for multiple isotypes. A number of hs3-binding transcription factors have been identified by EMSA, in- cluding octamer and NF-␬B family members, and Pax5. We have found that the binding of the transcription factor, Yin Yang 1 (YY1), to hs3 and to the ␮E1 site of the intronic enhancer, E␮, is induced in primary splenic B cells after ϳ48 h in response to LPS and other activators of class switch recombination. Transient transfection experiments in B cell lines indicate that YY1 is an activator of hs3. Interestingly, levels of YY1 expression are unchanged in resting and LPS-stimulated B cells. Mixing experiments followed by EMSA showed that a protein present in resting B cells prevented binding of YY1 to DNA. We found that recombinant retinoblastoma protein (Rb) inhibited binding of YY1 to hs3 in a dose-dependent manner, and we have identified complexes of Downloaded from endogenous YY1 with the Rb in resting B cells, but not in LPS-stimulated B cells. A difference in Rb phosphorylation state was also confirmed between resting (G0) B cells and LPS-stimulated B cells. These observations suggest that the interaction of YY1 with hypophosphorylated Rb in resting B cells prevents interaction of YY1 with DNA. After stimulation with class-switching activators, such as LPS, Rb becomes hyperphosphorylated and YY1 is released and can then bind to the hs3 enhancer and E␮. The Journal of Immunology, 2003, 170: 5549–5557. http://www.jimmunol.org/ uring B cell differentiation, the Igh locus undergoes In mice, hs3A and hs3B are arranged in a single ϳ25-kb in- unique DNA rearrangements and modifications, includ- verted repeat centered at hs1,2 (9, 10). Although targeted deletion D ing V(D)J joining, class switch recombination, and so- may have identified a distinctive role for hs3B as compared with matic hypermutation (1). These changes in the Igh locus are ex- hs3A, the sequences of hs3A (GenBank accession U65625) and quisitely regulated by a number of cis-acting elements, including hs3B (GenBank accession S74164) in mice are virtually identical, Ј ␮ Ј the 5 VH promoters, the intronic enhancer, E , and the 3 Igh and both enhancers are equally active in transcriptional assays (9). regulatory region, which is composed of four enhancers (DNase I Therefore, we have considered hs3A and hs3B to be functionally 4 hypersensitive site (hs) 3A, hs1, 2, hs3B, and hs4) (2). E␮ is interchangeable in our studies. Hs3A, hs1,2, and hs3B appear to 3 by guest on September 23, 2021 essential for early events in B cell differentiation, including V DJ comprise a distinct functional unit, becoming DNase I hypersen- ␮ joining and expression (3, 4), and recent experiments have sitive and active in transient transfection assays only later in B cell Ј shown that the Igh 3 enhancers are essential for H chain class development (9). In contrast, the most 3Ј enhancer, hs4, appears to switching. Targeted clean deletions of hs3B and hs4 (5), but not of be active throughout B cell differentiation (11, 12). hs3A or hs1,2 (6), resulted in defects in class switching to many The 3Ј Igh enhancers are regulated by an array of transcription isotypes at the level of germline transcription (GT). Hs3B and hs4 factors, including but not limited to Oct-1, Oct-2, NF-␬B, and together may also contribute to surface IgM expression in resting Pax5 (B cell-specific activating protein (BSAP)) (12–14). Pax5, in B cells (5) and are essential for maintaining high levels of ␥2b particular, functions as an early B cell-specific regulator of the mRNA expression in a plasma cell line (7). The 3Ј Igh enhancers hs1,2 and hs4 enhancers (14, 15). Additional motifs within the are also candidates for influencing the dysregulation of the expres- hs1,2 enhancer are bound inducibly to protein complexes after the sion of c-myc that occurs as a result of Igh:c-myc chromosomal ␬ translocations in Burkitt’s lymphoma, and mouse and human my- treatment of splenic B cells with LPS (NF- B), anti-IgM, or CD40 eloma cells (8). ligand (Jun-B, Elf-1) (16, 17). Little information is currently avail- able on the factors that regulate mouse hs3. Previous studies have predicted octamer sites (13) and Maf recognition elements within Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 hs3 (18). We wanted to identify transcription factors that might impact on Received for publication December 20, 2002. Accepted for publication March 21, 2003. a role of hs3 in CSR. B cells activated by LPS or anti-CD40 are The costs of publication of this article were defrayed in part by the payment of page stimulated to proliferate and to undergo class switch recombina- charges. This article must therefore be hereby marked advertisement in accordance tion (19). Various cytokines (i.e., IL-4, IFN-␥, TGF-␤, and IL-10) with 18 U.S.C. Section 1734 solely to indicate this fact. direct switching to particular isotypes by enhancing expression of 1 This work was supported by National Institutes of Health AI13509 and by an Albert Einstein Cancer Center Grant P30 CA13330. specific germline transcripts (19). In this study, we discovered the induction of an hs3 enhancer-binding protein, Yin Yang 1 (YY1), 2 Current address: Department of Hematology and Oncology, Children’s Hospital and Harvard Medical School, Boston, MA 02115. a zinc finger transcription factor, after ϳ48-h treatment of primary 3 Address correspondence and reprint requests to Dr. Barbara K. Birshtein, Depart- splenic B cells with LPS, LPS ϩ IL-4, and anti-CD40 ϩ IL-4. ment of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave- YY1 binding to the ␮E1 site of the intronic enhancer is also in- nue, Bronx, NY 10461. E-mail address: [email protected] duced. We find that YY1 is a transcriptional activator of the hs3 4 Abbreviations used in this paper: hs, DNase I hypersensitive site; BSAP, B cell- specific activating protein; GDI, guanine nucleotide dissociation inhibitor; GT, germ- enhancer, as has been demonstrated previously for the engagement line transcription; Rb, retinoblastoma protein; YY1, Yin Yang 1. of YY1 with the ␮E1 site of E␮ (20, 21). Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 5550 YY1 IS AN LPS-INDUCIBLE ACTIVATOR OF hs3 YY1 can function as a transcriptional repressor or activator (22), Plasmids and site-directed mutagenesis most likely reflecting the differential association of YY1 with its Murine hs3B was PCR amplified from the 13-kb C57BL/6 YAC subcloned many interaction partners. These include numerous histone with primers flanked by SmaI sites and inserted into the SmaI site of the deacetylases (23, 24) and histone acetyl transferases, such as p300, vector QM293luc (9), which contains the B cell-specific V␭1 promoter CREB binding protein (CBP), and p300/CBP-associated factor (14). The mutated hs3B monomer was constructed by performing two sep- Ј Ј (PCAF) (24). YY1 has been proposed to be a mammalian poly- arate PCR and ligating the resultant fragments. The hs3-5 primer (5 - gggccctctagaaccacatgcgatcta-3Ј) and mLRE antisense primer were used to comb protein, based on the extensive identity of its C-terminal amplify the 5Ј portion of hs3, and mLRE sense (5Ј-ccacactcgtgccttagaat DNA binding domain to the Drosophila pleiohomeotic protein tcccatgttctgtcccaa-3Ј) and hs3-3Ј primer (5Ј-cccgggatcattgagctccggctcta- (25). As such, YY1 interacts with the RYBP protein, which is 3Ј) were used to amplify the 3Ј portion of hs3. Mutated residues are in bold associated with a transcriptionally repressive polycomb complex type. Dimers of hs3B wt and mutant were generated by ligation of indi- vidual monomers for4htoovernight at 16°C, followed by gel isolation (26), and with YAF-2, which, although closely related to RYBP, is and ligation with SmaI-linearized QM293luc, as described above. The a coactivator of YY1 (27). Rous sarcoma virus-␤-galactosidase plasmid has been described (29). All YY1 has been reported to be constitutively expressed (22), and plasmids were purified using Qiagen (Valencia, CA) kits, as described by we confirmed this in resting and activated splenic B cells.
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