Mechanism of E47-Pip Interaction on DNA Resulting in Transcriptional Synergy and Activation of Immunoglobulin Germ Line Sterile Transcripts

Nagulapalli, Sujatha; Goheer, Aisha; Pitt, Leslie; McIntosh, Lawrence P.; Atchison, Michael L.

doi:10.1128/mcb.22.20.7337-7350.2002

Cited by 20 publications

(22 citation statements)

References 77 publications

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“…IRF-4 requires an interaction partner, such as PU.1, to efficiently bind DNA and activate transcription (63). It has recently been shown that E47 can bind to DNA cooperatively with IRF-4 to synergistically activate transcription of Ig germline transcription (64). Therefore it is possible that these types of transcription factor interactions could compensate for the loss of PU.1 and/or Spi-B activity.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Schweitzer

DeKoter

2004

The Journal of Immunology

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A number of presumptive target genes for the Ets-family transcription factor PU.1 have been identified in the B cell lineage. However, the precise function of PU.1 in B cells has not been studied because targeted null mutation of the PU.1 gene results in a block to lymphomyeloid development at an early developmental stage. In this study, we take advantage of recently developed PU.1−/−Spi-B−/− IL-7 and stromal cell-dependent progenitor B (pro-B) cell lines to analyze the function of PU.1 and Spi-B in B cell development. We show that contrary to previously published expectations, PU.1 and/or Spi-B are not required for Ig H chain (IgH) gene transcription in pro-B cells. In fact, PU.1−/−Spi-B−/− pro-B cells have increased levels of IgH transcription compared with wild-type pro-B cells. In addition, high levels of Igκ transcription are induced after IL-7 withdrawal of wild-type or PU.1−/−Spi-B−/− pro-B cells. In contrast, we found that Igλ transcription is reduced in PU.1−/−Spi-B−/− pro-B cells relative to wild-type pro-B cells after IL-7 withdrawal. These results suggest that Igλ, but not IgH or Igκ, transcription, is dependent on PU.1 and/or Spi-B. The PU.1−/−Spi-B−/− pro-B cells have other phenotypic changes relative to wild-type pro-B cells including increased proliferation, increased CD25 expression, decreased c-Kit expression, and decreased RAG-1 expression. Taken together, our observations suggest that reduction of PU.1 and/or Spi-B activity in pro-B cells promotes their differentiation to a stage intermediate between late pro-B cells and large pre-B cells.

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Section: Discussionmentioning

confidence: 99%

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Schweitzer

DeKoter

2004

The Journal of Immunology

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“…5D), because IRF-8 has recently been reported to participate in the activation of AID gene expression (15). It is also interesting that anti-IgM reduced the expression of IRF-4 mRNA, because IRF-4 has been shown to synergize with the E2A protein E47 at another promoter, the I promoter activating germ line I transcription, which is required for isotype class switching (28,29). In addition, IRF4-deficient B cells have been shown to display impaired expression of AID and lack class-switch recombination (30).…”

Section: Discussionmentioning

confidence: 99%

B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

Hauser

Sveshnikova

Wallenius

et al. 2008

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

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Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membranebound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca 2؉ ) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca 2؉ sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca 2؉ /calmodulin inhibition of E2A.activation-induced cytidine deaminase ͉ BCR ͉ calcium ͉ E2A P rocesses that diversify antibodies play a major role in protecting higher organisms from pathogens. Upon encountering antigens, antibody-expressing B-lineage lymphocytes adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, and gene conversion can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons (1, 2). Activationinduced cytidine deaminase (AID) is the antibody diversification enzyme that is essential for somatic hypermutation, gene conversion, and CSR (3-5). The mutagenic AID enzyme has to be tightly controlled, and both aberrant AID activity and chromosomal translocations involving switch regions of antibody genes are hallmark features of B-cell malignancies (2, 6-9).AID is specifically expressed in a subset of germinal center B-lymphocytes (10, 11). Specific stimulatory signals activate their proliferation and the diversification of the variable regions of their Ig genes, followed by expression of mutated surface Ig and selection of the mutated B-cell receptors (BCRs) for reactivity with antigen (12-14). E-protein, NF-B, Pax5, STAT6, and IRF-8 transcription factors participate in expression of the AID gene (15-18). The gene is induced by IL-4 and ligation of CD40, and, in mice, other inducers have also been identified, including LPS (11,17,19). Only ligation of CD45 has been reported to lead to signaling that inhibits AID gene expression, and this was shown to involve inhibition of signaling to STAT6 (19).In the present study, we show that a...

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“…IRF4 and Spi-B, when expressed in Abelson transformed pro-B cells, are sufficient to activate germline transcription (18). IRF4,8 have been found to interact with the E2A family of transcription factors to regulate activities of both Ig H chain intron enhancer and 3Ј enhancer (19,20). It has been shown that the interaction of IRF4 and E2A enhances binding affinity of E2A for the E3Ј enhancer.…”

mentioning

confidence: 99%

IFN Regulatory Factor 4 and 8 Promote Ig Light Chain κ Locus Activation in Pre-B Cell Development

Turetsky

Trinh

et al. 2006

The Journal of Immunology

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Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8−/−). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8−/− mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8−/− mice is not due to a lack of survival signal. IRF4,8−/− pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8−/− pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8−/− pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM+ B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8−/− pre-B cells, induces κ germline transcription, enhances V(D)J rearrangement activity at the κ locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the κ locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the κ locus.

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Mechanism of E47-Pip Interaction on DNA Resulting in Transcriptional Synergy and Activation of Immunoglobulin Germ Line Sterile Transcripts

Cited by 20 publications

References 77 publications

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins

IFN Regulatory Factor 4 and 8 Promote Ig Light Chain κ Locus Activation in Pre-B Cell Development

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