Regulation of the germline immunoglobulin Cγ1 promoter by CD40 ligand and IL-4: dual role for tandemNF-κB binding sites

Warren, Wendy D.; Roberts, Karen; Linehan, Leslie A.; Berton, Michael T.

doi:10.1016/s0161-5890(98)00114-x

Cited by 35 publications

(19 citation statements)

References 54 publications

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“…In our PTIP Ϫ B cells, the failure to switch to IgG1 is most likely due to a transcriptional defect of the ␥1 GLT. Activation of the ␥1 promoter appears to be mediated by NF-B (20,38) and STAT6 (21) binding near the GLT start site. We have shown significant increases in H3K4me3 at the GLT promoter regions in response to LPS/IL-4 stimulation.…”

Section: Discussionmentioning

confidence: 99%

Role of PTIP in Class Switch Recombination and Long-Range Chromatin Interactions at the Immunoglobulin Heavy Chain Locus

Schwab

Patel

Dressler

2011

Molecular and Cellular Biology

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How distal transcriptional enhancer sequences interact with proximal promoters is poorly understood within the context of chromatin. In this report, we have used the immunoglobulin heavy chain locus to address the role of the PTIP protein in transcription regulation and class switch recombination in B cells, a process that depends on regulated transcription and DNA recombination via Pax5 and distal 3 enhancer sequences. We first show that PTIP is recruited to a Pax5 binding site to promote histone H3 lysine 4 (H3K4) methylation. Using a CD19-Cre driver strain, we deleted PTIP in mature B cells. Loss of PTIP inhibited class switch recombination by suppressing transcription and histone H3K4 methylation at the germ line transcript promoters. In the absence of PTIP, Pax5 binding to the promoter regions is reduced and long-range chromatin interactions between the distal enhancer at the 3 regulatory region and the germ line transcript promoters are not detected. We propose a model whereby PTIP stabilizes the Pax5 DNA interactions that promote chromatin looping and regulate transcriptional responses needed for class switch recombination.Long-range interactions between distal enhancers and promoters are known to regulate many multigene loci through DNA looping mechanisms that bring enhancer sequences and their respective binding proteins close to a transcription start site (14,18,27). The immunoglobulin heavy chain locus (IgH) is an example of a large locus with multiple transcripts, splice variants, regulatory elements, and genomic rearrangements that can produce different proteins in response to a variety of signaling inputs. In B lymphocytes, class switch recombination (CSR) rearranges the immunoglobulin heavy chain (IgH) locus such that new constant regions replace the IgM isotype (35). In response to specific stimuli, CSR requires the initiation of germ line transcripts (GLTs) upstream of the new constant region, before double-strand break formation and recombination. B cell differentiation and IgH transcription depend on the 3Ј enhancer sequences (12), which are known to interact with the switch regions through a chromatin looping mechanism (17).The Pax5 gene, a member of the paired-box (Pax) gene family first identified as homologues of the Drosophila melanogaster paired and gooseberry segmentation genes, encodes a protein that is essential for B cell specification and immunoglobulin gene expression (8). Genetic loss-of-function experiments in mice provide strong evidence that Pax5 is necessary not only for the transition from pre-B cell to IgM-positive B cells (36) but also for the maintenance of B cell phenotypic stability (24) and for isotype switching and generation of Igsecreting B cells (15). Within the IgH locus, Pax5 binds to the 3Ј enhancer (23), although how Pax5 contributes to chromatin looping and GLT regulation is unclear. Pax5 is a member of the Pax2/5/8 subfamily, whose amino-terminal DNA binding domains are virtually identical and whose carboxy-terminal sequences share large regions of identity (2...

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Section: Discussionmentioning

confidence: 99%

Role of PTIP in Class Switch Recombination and Long-Range Chromatin Interactions at the Immunoglobulin Heavy Chain Locus

Schwab

Patel

Dressler

2011

Molecular and Cellular Biology

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“…Similar to the endogenous transcripts, treatment with CD40L and IL-4 activates transcription from both promoters, and CD40L alone activates the mouse GL ␥1 promoter somewhat better than the ⑀ promoter (35)(36)(37). In addition, the ⑀ promoter can be induced by IL-4 alone, whereas the ␥1 promoter cannot be (33,36,38).…”

Section: U Pon Activation By Ag or Mitogens Igmmentioning

confidence: 94%

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Chunsheng

Stavnezer

2001

The Journal of Immunology

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Before Ig class switching, RNA transcription through the specific S regions undergoing recombination is induced by cytokines and other activators that induce and direct switching. The resulting germline (GL) transcripts are essential for switch recombination. To understand the differential regulation of mouse IgG1 and IgE, we compared the promoters for GL γ1 and ε transcripts. We addressed the question of why the promoter that regulates GL ε transcription is more responsive to IL-4 than the γ1 promoter and also why GL ε transcription is more dependent on IL-4 than is γ1 transcription. We found that the IL-4-responsive region of the GL ε promoter is more inducible than that of the γ1 promoter, although each promoter contains a binding site for the IL-4-inducible transcription factor Stat6, located immediately adjacent to a binding site for a basic region leucine zipper (bZip) family protein. However, the arrangement and sequences of the sites differ between the ε and γ1 promoters. The GL ε promoter binds Stat6 with a 10-fold higher affinity than does the γ1 promoter. Furthermore, the bZip elements of the two promoters bind different transcription factors, as the GL ε promoter binds and is activated by AP-1, whereas the γ1 promoter binds and is activated by activating transcription factor 2. C/EBPβ and C/EBPγ also bind the γ1 bZip element, although they inhibit rather than activate transcription. However, inhibition of promoter activity by C/EBPβ does not require the bZip element and may instead occur via inhibiting the activity of NF-κB.

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“…Another IL-4-mediated effect which has been attributed to Stat6 activation is the induction of isotype switching to IgE production upon costimulation of B cells through CD40 (5,6,42).…”

Section: Cd43mentioning

confidence: 99%

Interleukin-4 Receptor–Stat6 Signaling in Murine Infections with a Tissue-Dwelling Nematode Parasite

2001

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Regulation of the germline immunoglobulin Cγ1 promoter by CD40 ligand and IL-4: dual role for tandemNF-κB binding sites

Cited by 35 publications

References 54 publications

Role of PTIP in Class Switch Recombination and Long-Range Chromatin Interactions at the Immunoglobulin Heavy Chain Locus

Role of PTIP in Class Switch Recombination and Long-Range Chromatin Interactions at the Immunoglobulin Heavy Chain Locus

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Interleukin-4 Receptor–Stat6 Signaling in Murine Infections with a Tissue-Dwelling Nematode Parasite

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