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Silencer Elements Controlling the B29 (Ig␤) Promoter Are Neither Promoter- Nor Cell-Type-Specific

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Silencer Elements Controlling the B29 (Ig␤) Promoter Are Neither Promoter- Nor Cell-Type-Specific Proc. Natl. Acad. Sci. USA Vol. 94, pp. 12314–12319, November 1997 Biochemistry Silencer elements controlling the B29 (Igb) promoter are neither promoter- nor cell-type-specific CINDY SUE MALONE*, SIDNE A. OMORI*†, AND RANDOLPH WALL*‡ *Molecular Biology Institute and Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095 Communicated by David S. Eisenberg, University of California, Los Angeles, CA, July 11, 1997 (received for review May 9, 1997) ABSTRACT The murine B29 (Igb) promoter is B cell combinatorial activities of this cassette of different transcrip- specific and contains essential SP1, ETS, OCT, and Ikaros tion factors (11, 20). motifs. Flanking 5* DNA sequences inhibit B29 promoter The current study focuses on the B29 regulatory region 59 of activity, suggesting this region contains silencer elements. the murine minimal B29 promoter. Deletion analyses of the Two adjacent 5* DNA segments repress transcription by the B29 gene 59 flanking region revealed two adjacent regions with murine B29 promoter in a position- and orientation- significantly lower transcriptional activity than the minimal independent manner, analogous to known silencers. Both promoter, suggesting the presence of silencer elements. Si- these 5* segments also inhibit transcription by several heter- lencers are functionally defined cis-acting regulatory DNA ologous promoters in B cells, including mb-1, c-fos, and human elements that down-regulate gene transcription. They gener- B29. These 5* segments also inhibit transcription by the c-fos ally exhibit activity in either orientation, may be either posi- promoter in T cells suggesting they are not B cell-specific tion-dependent or -independent, and may or may not affect elements. DNase I footprint analyses show an approximately heterologous promoters (13, 21, 22). When tested in transient 70-bp protected region overlapping the boundary between the transfections, two unique DNA segments isolated from the two negative regulatory DNA segments and corresponding to inhibitory region 59 of the minimal promoter, designated binding sites for at least two different DNA-binding proteins. 2354y2165 and 2565y2355 segments, inhibited transcription Within this footprint, two unrelated 30-bp cis-acting DNA of the murine B29 minimal promoter in a position- and motifs (designated TOAD and FROG) function as position- orientation-independent manner. Both DNA segments also and orientation-independent silencers when located directly inhibited transcription from heterologous promoters, further 5* of the murine B29 promoter. These two silencer motifs act defining them as transcriptional silencers. DNA footprinting cooperatively to restrict the transcriptional activity of the B29 showed a 70-bp protected region overlapping the 2354y2355 promoter. Neither of these motifs resembles any known si- boundary of these two segments. Within this protected region, lencers. Mutagenesis of the TOAD and FROG motifs in their two unrelated DNA sequences, designated the TOAD and respective 5* DNA segments eliminates the silencing activity of FROG motifs, exhibited both position- and orientation- these upstream regions, indicating these two motifs as the independent silencing of the B29 promoter. Electrophoretic principal B29 silencer elements within these regions. mobility shift assays (EMSA) indicated that the TOAD and FROG motifs interact with distinct non-tissue-specific nuclear The B29 gene is strictly B cell-specific and expressed at all DNA-binding proteins. Site-directed mutagenesis of these two stages of B cell differentiation (1). The B29 gene product, also motifs in the context of their respective 59 DNA segments called Igb, is disulfide-linked to the mb-1 gene product Iga and alleviated transcriptional silencing equivalent to successive this heterodimeric complex is associated with all Ig isotypes to deletion of the complete segments, thereby affirming that form the B cell-receptor complex (2–5). The B29–mb-1 het- TOAD and FROG are the principle 59 silencer motifs in this erodimer plays a central and critical role in B cell development. region acting on the B29 promoter. Specific events in B cell development that are controlled by B29–mb-1 heterodimers include allelic exclusion (6, 7) and the pre-B cell transition marked by cell surface translocation of MATERIALS AND METHODS IgM (3, 4, 6, 8). Signal transduction through cross-linked IgM Plasmid Construction and Mutagenesis. The B29 minimal is also controlled by B29–mb-1 heterodimers (for review, see (2164) promoter and 59 deletion constructs with endpoints at ref. 9). In addition, B29 knock-out mice (i.e., Igb2/2) produce positions 21230, 2890, 2719, 2565, 2354, and 2293 were pro-B cells that fail to progress beyond the DJH stage of cloned in pCAT Basic (Promega). In all constructs, the B29 rearrangement, suggesting B29 is essential for VDJH recom- endogenous ATG was destroyed, leaving the translation start bination resulting in functional m chain production (10). site as the first methionine codon of the chloramphenicol We have previously identified and characterized the B29 acetyltransferase (CAT) gene. B29 59 segments (2354y2165 minimal promoter to resolve the features controlling its B cell and 2565y2355) were generated by PCR and cloned 59 of the specificity (11). The B29 promoter is a TATA-less promoter following promoters: murine B29 (2164), c-fos (271) (23), containing essential cis-acting OCT, ETS, SP1, and Ikaros human B29 (2193) (24), and murine mb-1 (2-252; provided motifs (11). A similar spectrum of motifs is present in the by Rudolph Grosschedl, University of California at San Fran- promoters of other TATA-less genes expressed in lymphocytes cisco) in pCAT Basic (Promega). B29 59 segments (2354y including ETS-1 (12), bcl-2 (13), mb-1 (14), TdT (15), VpreB l (16), 5 (17), CD19 (18), and pp52 (19). The strict B cell Abbreviations: CAT, chloramphenicol acetyltransferase; EBF, early B specificity of the B29 minimal promoter is determined by the cell factor; EMSA, electrophoretic mobility-shift assay; NRE, negative regulatory element. The publication costs of this article were defrayed in part by page charge Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF002279). payment. This article must therefore be hereby marked ‘‘advertisement’’ in †Present address: Department of Biology, University of California at accordance with 18 U.S.C. §1734 solely to indicate this fact. San Diego, La Jolla, CA 92093. © 1997 by The National Academy of Sciences 0027-8424y97y9412314-6$2.00y0 ‡To whom reprint requests should be addressed. e-mail: PNAS is available online at http:yywww.pnas.org. [email protected]. 12314 Downloaded by guest on September 27, 2021 Biochemistry: Malone et al. Proc. Natl. Acad. Sci. USA 94 (1997) 12315 2165 and 2565y2355) were also cloned downstream of CAT in vectors containing either the B29 ( 2164) or the (2354) promoter segments. The synthetic DNA oligonucleotides [5 9- CTCTTCCAGAGCAAGGCAACCACAGGAGACC-39 (2349y2321, i.e., TOAD) and 59-GGTGTGCATTTAGCTA- AATTCCCCA-39 (2381y2356, i.e., FROG)] were cloned in single and multiple copies and in both orientations 59 of B29 promoter constructs (positions 2164, 2354, and 2565). Mu- tagenized constructs were generated by using the Quik-Change mutagenesis kit (Stratagene) and the following oligonucleotides: mTOAD (positions 2335, 2336), 59-CTCTTCCAGAGCAAG- ttAACCACAGGAGACCA-39, and mFROG (positions 2369, 2373), 59-GGTGTGCAgTTAaCTAAATTCCCCA-39. Other TOAD motif mutations at bases 2329, 2331, 2333, and 2338 had no effect on silencing activity (data not shown). DNA Transfections and CAT Assays. M12 B cell line was transfected by the DEAE-dextran method (25). Cells were cotransfected with 5 mg of CAT reporter plasmid and 1 mgof FIG. 1. B29 minimal promoter activity is modulated by 59 flanking pRSV-luciferase. Extracts were prepared and assayed as in ref. sequences. Transient transfections to detect transcriptional expression 11 with the exception of quantification by PhosphorImager of sequential B29 promoter deletion constructs were carried out in the (Molecular Dynamics) analysis. Results were normalized to M12 B cell line. Deletion constructs are identified by nucleotide luciferase activity and are the average 6 SD of at least four numbers with respect to the major start site of transcription (11). The transfections using at least two preparations of DNA. Absolute activity of each deletion construct is expressed as a percentage of the fold inductions for each promoter construct ranged from 8- to CAT activity obtained with the B29 minimal (2164) promoter con- 40-fold (muB29), 8- to 30-fold (huB29), 6- to 20-fold (mb-1), struct (100%). 45- to 200-fold (c-fos M12), and 12- to 50-fold (c-fos BW5147) Overall, these silencer constructs exhibited activities compa- over vector alone (pCAT basic). rable to the B29 (2354) promoter. Neither the B29 2354 Nuclear Extracts and DNA-Binding Assays. Preparation of y crude nuclear extracts from cell lines and DNase I footprinting 2165 nor the 2565y2355 segment showed further inhibitory were performed as described (26). The DNase I footprinting effects on CAT reporter gene activity when placed upstream probe was generated by 59 end labeling with [g-32P]ATP at the of the B29 position 2354 and 2565 promoters (data not ClaI site of the pCR-Script B29 2411y2293 PCR fragment shown). Thus these data suggest the B29 2354y2165 and construct, followed by digestion with
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