A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation

Makar, Karen W.; Ulgiati, Daniela; Hagman, James; Holers, V. Michael

doi:10.1093/intimm/13.5.657

Cited by 39 publications

(31 citation statements)

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“…The human CR2 gene (OMIM 120650) encodes a membrane glycoprotein, consisting of 15 repeating structures termed short consensus repeats (SCRs), that is expressed on mature B cells and follicular dendritic cells, as well as an alternatively spliced 16 SCR variant that is expressed primarily on follicular dendritic cells (13). Its relative expression is primarily controlled at the level of transcription by the proximal promoter (14)(15)(16)(17), and cell and lineage specificity of expression is regulated by an intronic silencer (18,19). CR2 binds C3 degradation products covalently bound to antigen in the process of complement activation, as well as EBV (20), the immunomodulatory protein CD23 (21), and IFN-␣ (22).…”

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Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Boackle

Hanvivadhanakul

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P ‫؍‬ 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P ‫؍‬ 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5 untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.linkage ͉ disease susceptibility ͉ antoimmunity ͉ single-nucleotide polymorphisms ͉ syntenic conservation

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Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Boackle

Hanvivadhanakul

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Both genes have been found to be controlled, via reporter assays, by two distinct regions of the gene: the proximal promoter regions and sequences within the first intron. The human CD21 gene has been shown to possess a number of functional sites, including Sp1, AP1, AP2, and E box sites proximal to the TATA box sequence, and NF-B and heterogeneous ribonucleoprotein sites further upstream (Ϫ531 and Ϫ495 relative to the transcription induction site, respectively) (13)(14)(15)(16)(17)(18)(19). The mouse CD21 promoter possesses a functional Oct-1 site (equal binding via EMSA with T and B cell nuclear extracts), a consensus Pax5 binding site (showing a B cell-specific EMSA pattern), and a conserved NF-B site (also showing equal binding via EMSA with T and B cell nuclear extracts) all within the first 280 bp of the promoter region (7, 20 -22).…”

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“…Transfection of human and mouse CD21 promoter reporter constructs into T (CD21 nonexpressing) and B cell lines (expressing cells) showed virtually identical reporter expression levels (7,13,14,22). However, when the first intron sequences were added to such constructs, the expression of the CD21 promoter constructs was dramatically reduced in T cells but unaltered in B cells.…”

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“…However, when the first intron sequences were added to such constructs, the expression of the CD21 promoter constructs was dramatically reduced in T cells but unaltered in B cells. Analyses with the human intronic sequence localized this tissue-specific repressor element, dubbed CRS (CR2 silencer), to a single RBP-J (CBF1) binding site within the intron (14). Transfection of human K562 cells (which normally do not express CD21) with a reporter construct demonstrated silencing of such constructs only with an intact CBF1 site.…”

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Defining In Vivo Transcription Factor Complexes of the Murine CD21 and CD23 Genes

Debnath

Roundy

Weis

et al. 2007

The Journal of Immunology

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The expression of the CD21 and CD23 genes is coincident with differentiation from transition 1 B cells (T1) to transition 2 B cells (T2). To define constituents controlling CD21 and CD23 expression, we conducted chromatin immunoprecipitation analyses for candidate transcription factors. We found constitutive binding of Oct-1, NFAT species, YY1, NF-κB-p52, Pax5, E2A, and RBP-Jκ to CD21 sequences and NF-κB-p52, Pax5, NFAT species, E2A, and RBP-Jκ to CD23 promoter sequences. Splenic T and B cell subsets displayed constitutive binding of YY1, NF-κB-p52, Pax5, and Oct-1 proteins to CD21 sequences in B cells but no specific binding of NFATc3 or Pax5 in T cells. Similarly, CD23 sequences demonstrated constitutive binding of NF-κB-p52 in splenic T and B cells but only Pax5 in B cells. Of the various NFAT species, only a subset were found forming constitutive DNA/protein complexes with the CD21, CD23, and IL-2 gene sequences. Maturing B cells in the marrow possess stable Pax5 complexes on CD19, CD21, and CD23 gene promoters in the nuclei of such cells, even though only CD19 is expressed. The similarity of genetic controlling elements between the CD21 and CD23 genes does not suggest a mechanism for alternative regulation of these genes; however, separation of splenic B cell subsets into T1, T2, marginal zone (MZ), and mature follicular B cells, followed by quantitative RT-PCR, demonstrated the lack of appreciable CD23 transcripts in CD21+ MZ cells. We propose an alternative derivation of MZ cells as maturing directly from T1 cells, leaving CD23 transcriptionally inactive in that lineage of cells.

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“…We have shown that the cell-and stage-specific expression of human CR2 is controlled by an intronic transcriptional silencer, designated the CR2 silencer. Use of a stable transfection system and transgenic mice has shown that the CR2 silencer element in conjunction with the CR2 proximal promoter is able to repress transcription in CR2-negative cell lines and tissues (14,15). Recently, we have also demonstrated the existence of a cell type-specific repressor element within the CR2 proximal promoter that is critical for inhibiting expression in CR2 nonexpressing cell lines (16).…”

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Functional Analysis of the Human Complement Receptor 2 (CR2/CD21) Promoter: Characterization of Basal Transcriptional Mechanisms

Ulgiati

Pham

Holers

2002

The Journal of Immunology

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Human complement receptor (CR) type 2 (CR2/CD21) is a 145-kDa membrane protein encoded within the regulators of complement activation gene cluster localized on human chromosome 1q32. Understanding the mechanisms that regulate CR2 expression is important because CR2 is expressed during specific stages of B cell development, and several lines of evidence suggest a role for altered CR2 function or expression in a number of autoimmune diseases. Additionally, even modest changes in CR2 expression are likely to affect relative B cell responses. In this study we have delineated the transcriptional requirements of the human CR2 gene. We have studied the human CR2 proximal promoter and identified sites important for controlling the level of transcription in CR2-expressing cells. We have determined that four functionally relevant sites lie within very close proximity to the transcriptional initiation site. These sites bind the transcription factors USF1, an AP-2-like transcription factor, and Sp1.

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A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation

Cited by 39 publications

References 43 publications

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Defining In Vivo Transcription Factor Complexes of the Murine CD21 and CD23 Genes

Functional Analysis of the Human Complement Receptor 2 (CR2/CD21) Promoter: Characterization of Basal Transcriptional Mechanisms

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