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Repressor Critically Dependent on a Cell Type-Specific CR2/CD21 CR2/CD21 Proximal Promoter Activity Is Critically Dependent on a Cell Type-Specific Repressor This information is current as Daniela Ulgiati and V. Michael Holers of September 25, 2021. J Immunol 2001; 167:6912-6919; ; doi: 10.4049/jimmunol.167.12.6912 http://www.jimmunol.org/content/167/12/6912 Downloaded from References This article cites 39 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/167/12/6912.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 25, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. CR2/CD21 Proximal Promoter Activity Is Critically Dependent on a Cell Type-Specific Repressor1 Daniela Ulgiati† and V. Michael Holers2*† Transcription of the human complement receptor type 2 (CR2/CD21) gene is controlled by both proximal promoter and intronic elements. CR2 is primarily expressed on B cells from the immature through mature cell stages. We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. This repressor sequence is shown by linker scanning mutagenesis to comprise an E box motif. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny. The Journal of Immunology, 2001, 167: 6912–6919. Downloaded from uman complement receptor type 2 (CR2;3 CD21) is a factor 1 (CBF1), a member of the developmentally important 145-kDa protein encoded within the regulators of the Notch signaling pathway. Mutation of this site results in loss of H complement activation gene cluster localized on human function of the silencer and strongly suggests that CBF1 plays a chromosome 1q32 (1). CR2 is the receptor for complement acti- role in controlling human CR2 expression (19). Furthermore, it vation fragments of C3, specifically, iC3b, C3dg, and C3d (2, 3). was shown that the silencer was unable to repress a heterologous http://www.jimmunol.org/ Additionally, CR2 is the receptor for the EBV and mediates EBV promoter, suggesting specificity for proximal promoter sites. Sim- infection by binding the membrane protein, gp350/220 (4, 5). Hu- ilarly, in the mouse, CR2 expression is regulated by an intronic man CR2 is also the B cell receptor for CD23 (6) and possibly silencer (20) that also requires CR2 proximal promoter sites for IFN-␣ (7). appropriate function (21). Human CR2 is primarily expressed during later stages of B cell In the studies reported herein, we have further analyzed the hu- ontogeny (8); however, it is also expressed on follicular dendritic man CR2 proximal promoter to identify cell type-specific elements cells (9), epithelial cells (10), some thymocytes (11), and a small that could act as putative interaction sites for the CR2 intronic subset of CD4ϩ and CD8ϩ peripheral T cells (12, 13). Within the silencer. We demonstrate the presence of a cell type-specific re- B cell lineage, CR2 is only found on immature and mature B cells, pressor that shows broad lineage- and stage-specific utilization. by guest on September 25, 2021 and its expression begins at approximately the same stage as IgD and CD23 (8, 14). It has been shown that CR2 is up-regulated after Materials and Methods B cells escape negative selection and migrate to the periphery Cell lines and culture conditions (15–17). All human cell lines used in these experiments were obtained from Amer- Previously, we have shown that cell- and stage-specific expres- ican Type Culture Collection (Manassas, VA). Cells lines were maintained sion of human CR2 is controlled by an intronic transcriptional at 37°C with 5% CO2 in RPMI 1640 with L-glutamine supplemented with silencer, designated the CRS (CR2 silencer). The use of a stable 10% FBS, 100 ␮g/ml streptomycin, and 100 IU/ml penicillin. transfection system and transgenic mice has shown that the CRS Creation and confirmation of mutant CR2 promoter/luciferase element, in conjunction with the CR2 proximal promoter, is able to fusion constructs repress transcription in CR2-negative cell lines and tissues (18). An NheI/XhoI fragment of the CR2 promoter containing nt Ϫ315/ϩ75 was Recent studies have further defined the CRS element and have cloned into the luciferase reporter pGL3-basic vector (CLONTECH Lab- shown a sequence within the silencer crucial to its function. This oratories, Palo Alto, CA). Site-directed mutagenesis was performed using sequence binds the transcriptional repressor C-promoter binding the Quickchange mutagenesis kit (Stratagene, La Jolla, CA), which enabled the incorporation of MluI restriction sites extending 3Ј from positions Ϫ140 (Sp1), Ϫ90 (AP1), Ϫ81 (AP2), Ϫ60 (E box 2) and Ϫ47 (E box 1). *Departments of Immunology and Medicine, and †Division of Rheumatology, Uni- The accuracy of all constructs created was assured by both restriction en- versity of Colorado Health Sciences Center, Denver, CO 80262 zyme digestion and nucleotide sequence analysis. Received for publication August 15, 2001. Accepted for publication October Creation and analysis of mutant CR2 linker scanning constructs 16, 2001. The costs of publication of this article were defrayed in part by the payment of page Linker scanning mutagenesis was performed using the Quickchange mu- charges. This article must therefore be hereby marked advertisement in accordance tagenesis kit (Stratagene). Incorporation of MluI restriction sites was made with 18 U.S.C. Section 1734 solely to indicate this fact. across the E box 2 motif at intervals of ϳ2 bp. An internal deletion con- Ϫ Ϫ 1 This work was supported by the Smyth Professorship (to V.M.H.), National Insti- struct was also made by use of a primer that lacked bp 67 to 61 of the tutes of Health Grant RO1AI31105 (to V.M.H.), and an Arthritis Foundation post- CR2 promoter. All constructs made were confirmed by nucleotide se- doctoral fellowship grant (to D.U.). quence analysis. 2 Address correspondence and reprint requests to Dr. V. Michael Holers, Division of Transfection and measurement of promoter/reporter gene activity Rheumatology, Campus Box B-115, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: [email protected] Before each transfection, cells were split and grown in log phase to ϳ5 ϫ 5 3 Abbreviations used in this paper: CR2, complement receptor type 2; HLH; helix- 10 cells/ml. Cells were then transfected using the Qiagen Superfect trans- loop-helix; bHLH, basic HLH; CBF1, C-promoter binding factor 1; CRS, CR2 si- fection reagent according to the manufacturer’s specifications with plasmid lencer; LS, linker scanning. DNA prepared using Qiagen Maxiprep-500 columns (Qiagen, Valencia, Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 6913 CA). Briefly, 10 ␮g of plasmid DNA and 300 ng of pRL-thymidine kinase normalized transcriptional activity (vs Renilla internal control) control vector were complexed in combination with Superfect reagent for was 5.272 Ϯ 1.374 (n ϭ 10) for the Daudi cell line and 5.065 Ϯ 10 min at room temperature. The transfection complexes were then added 0.271 for the Raji (n ϭ 5) cell line. This is in contrast to two non-B dropwise to the cells that had been plated in 5 ml of medium in a six-well tray at a concentration of 5 ϫ 105–1 ϫ 106 cells/ml. The cells were then cell lines (that do not express CR2), K562 and U937, which dem- incubated at 37°C for 48 h following transfection. Cell lysates from the onstrated much lower promoter activity (0.627 Ϯ 0.157 (n ϭ 11) transfected cells were prepared and assayed for both firefly and Renilla and 0.281 Ϯ 0.065 (n ϭ 4), respectively; Fig. 1). luciferase according to the manufacturer’s instructions (Promega, Madison, To determine whether the low level of transcriptional activity WI). All transfection data shown are the mean of 3–10 independent trans- fections, with n values shown in each experiment. Additionally, multiple was limited to non-B cells that do not express CR2 or whether it preparations of DNA were used and yielded essentially identical results. was also present in cells of the B cell lineage that do not express Promoter activity is expressed as relative firefly luciferase activity normal- CR2, the Ϫ315/ϩ75 construct was transiently transfected into a ized against Renilla luciferase activity. pre-B cell line (Fig. 1, Reh). These results also demonstrated a low Ϯ EMSA relative level of transcription in this cell line (0.563 0.115). Overall, these results show that even though the CR2-proximal 7 Approximately 8 ϫ 10 cells were used to make nuclear extracts according promoter is active in all cell lines tested compared with the pGL3 to a standard method (22).
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