The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

Dunnick, Wesley A.; Shi, Jian; Holden, Victoria; Fontaine, Clinton; Collins, John T.

doi:10.4049/jimmunol.1003108

Cited by 11 publications

(8 citation statements)

References 35 publications

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“…As the GL IgG2a/c transcripts are less abundant than the GL IgG1or IgG3 transcripts, 23 we used nested PCR for γ2 GLT detection. GL IgG2a/c transcripts were not detected in unstimulated B cells.…”

Section: Resultsmentioning

confidence: 99%

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response

et al. 2012

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IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5−/− B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5−/− B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5−/− B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.

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Section: Resultsmentioning

confidence: 99%

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response

et al. 2012

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“…3D1, lane 21). The promoter regions for germline transcripts have a major role in determining the cytokine specificity of CSR (1, 41). …”

Section: Discussionmentioning

confidence: 99%

Enhancement of Antibody Class-Switch Recombination by the Cumulative Activity of Four Separate Elements

Dunnick

Shi

Zerbato

et al. 2011

The Journal of Immunology

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Class switch recombination of antibody isotype is mediated by a recombinational DNA deletion event, and must be robustly upregulated during antigen-driven differentiation of B cells. The enhancer region 3′ of the Cα gene is important for the upregulation of switch recombination. Using a transgene of the entire heavy chain constant region locus, we now demonstrate that it is the four 3′ enhancer elements themselves (a total of 4.7 kb) that are responsible for the upregulation, rather than the 24 kb of DNA in between them. Neither allelic exclusion nor transgenic μ expression is reduced by deletion of the four 3′ enhancers. We also test deletions of two or three of the 3′ enhancers, and show that deletion of more 3′ enhancers results in a progressive reduction in both switch recombination and germline transcription of all heavy chain genes. Nevertheless, we find evidence for special roles for some 3′ enhancers--different heavy chain genes are affected by different 3′ enhancer deletions. Thus, we find that the dramatic induction of class switch recombination during antigen-driven differentiation is the result of an interaction among four separated regulatory elements.

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“…Isotype class switching in activated B cells illustrates this capability. The location of class switch recombination (CSR) is determined by lymphokine signals that control the transcription of "switch" regions where the necessary double-stranded breaks occur [190,191]. In other words, the immune system instructs the activated B cells which class of antibody to produce in response to a particular infection by targeting a specific DNA breakage-and-joining process.…”

Section: Targeting Of Nge and Mobile Elementsmentioning

confidence: 99%

How life changes itself: The Read–Write (RW) genome

Shapiro

2013

Physics of Life Reviews

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The genome has traditionally been treated as a Read-Only Memory (ROM) subject to change by copying errors and accidents. In this review, I propose that we need to change that perspective and understand the genome as an intricately formatted Read-Write (RW) data storage system constantly subject to cellular modifications and inscriptions. Cells operate under changing conditions and are continually modifying themselves by genome inscriptions. These inscriptions occur over three distinct time-scales (cell reproduction, multicellular development and evolutionary change) and involve a variety of different processes at each time scale (forming nucleoprotein complexes, epigenetic formatting and changes in DNA sequence structure). Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences.

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The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

Cited by 11 publications

References 35 publications

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response

Enhancement of Antibody Class-Switch Recombination by the Cumulative Activity of Four Separate Elements

How life changes itself: The Read–Write (RW) genome

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