Dataset Information

Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells.

ABSTRACT: Complement receptor 2 (CR2/CD21) is predominantly expressed on the surface of mature B cells where it forms part of a coreceptor complex that functions, in part, to modulate B-cell receptor signal strength. CR2/CD21 expression is tightly regulated throughout B-cell development such that CR2/CD21 cannot be detected on pre-B or terminally differentiated plasma cells. CR2/CD21 expression is upregulated at B-cell maturation and can be induced by IL-4 and CD40 signaling pathways. We have previously characterized elements in the proximal promoter and first intron of CR2/CD21 that are involved in regulating basal and tissue-specific expression. We now extend these analyses to the CR2/CD21 core promoter. We show that in mature B cells, CR2/CD21 transcription proceeds from a focused TSS regulated by a non-consensus TATA box, an initiator element and a downstream promoter element. Furthermore, occupancy of the general transcriptional machinery in pre-B versus mature B-cell lines correlate with CR2/CD21 expression level and indicate that promoter accessibility must switch from inactive to active during the transitional B-cell window.

SUBMITTER: Taylor RL

PROVIDER: S-EPMC4711682 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells.

Taylor Rhonda L RL Cruickshank Mark N MN Karimi Mahdad M Ng Han Leng HL Quail Elizabeth E Kaufman Kenneth M KM Harley John B JB Abraham Lawrence J LJ Tsao Betty P BP Boackle Susan A SA Ulgiati Daniela D

Cellular & molecular immunology 20150202 1

Complement receptor 2 (CR2/CD21) is predominantly expressed on the surface of mature B cells where it forms part of a coreceptor complex that functions, in part, to modulate B-cell receptor signal strength. CR2/CD21 expression is tightly regulated throughout B-cell development such that CR2/CD21 cannot be detected on pre-B or terminally differentiated plasma cells. CR2/CD21 expression is upregulated at B-cell maturation and can be induced by IL-4 and CD40 signaling pathways. We have previously c ...[more]

PMID: 25640655

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Project description:Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of the B cell coreceptor with CD19 and CD81. Differential splicing of transcripts from the mouse Cr2 gene generates isoforms with both shared and unique complement binding capacities and cell-type expression. In mouse models, genetic depletion of Cr2 causes either a delay or complete prevention of prion disease, but the relative importance of CD35 versus CD21 in promoting prion disease remains unknown. Here we show that both isoforms act as high-affinity cell surface prion receptors. However, mice lacking CD21 succumbed to terminal prion disease significantly later than mice lacking CD35 or wild-type and hemizygous mice. CD21-deficient mice contained fewer splenic prions than CD35 knockout mice early after infection that contributed to delayed prion neuroinvasion and terminal disease, despite forming follicular networks closer to proximal nerves. While we observed no difference in B cell networks, PrPC expression, or number of follicles, CD21-deficient mice formed more fragmented, less organized follicular networks with fewer Mfge8-positive FDCs and/or tingible body macrophages (TBM?s) than wild-type or CD35-deficient mice. In toto, these data demonstrate a more prominent role for CD21 for proper follicular development and organization leading to more efficient lymphoid prion replication and expedited prion disease than in mice expressing the CD35 isoform. IMPORTANCE Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer's disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis.

Dataset Information

Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells.

Publications

Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells.

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