E-proteins directly regulate expression of activation-induced deaminase in mature B cells

Sayegh, Camil E.; Quong, Melanie W.; Agata, Yasutoshi; Murre, Cornelis

doi:10.1038/ni923

Cited by 213 publications

(238 citation statements)

References 49 publications

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“…Retroviral overexpression of ID3 in activated B cells implicated E-proteins in the control of CSR (Quong et al, 1999) and AID expression (Sayegh et al, 2003). Here, we have significantly extended these findings by demonstrat-ing that E-proteins control CSR by regulating Igh germline transcription through the 3′RR domain and by controlling Aicda expression through multiple enhancers.…”

Section: Discussionsupporting

confidence: 55%

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

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1201B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens. This enormous adaptive potential of B cells is brought about by V(D)J recombination of the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) genes in early B cell development, and by subsequent affinity maturation of the Ig heavy chain in late B cell differentiation (Victora and Nussenzweig, 2012). Somatic hypermutation alters the antigen-binding V H sequences of the Ig heavy-chain, whereas class switch recombination (CSR) exchanges the C H exons to generate Ig isotypes with distinct effector functions (Chaudhuri and Alt, 2004). Whereas the activation-induced deaminase (AID) is an essential regulator of both processes (Muramatsu et al., 2000), somatic hypermutation only takes place in germinal centers (GCs), which are formed upon antigen exposure by the interplay of T follicular helper (Tfh) cells and follicular (FO) B cells in secondary lymphoid organs (Victora and Nussenzweig, 2012). Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al., 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.Basic helix-loop-helix (bHLH) transcription factors can be subdivided into different classes based on biochemical and functional properties (Murre, 2005). Class I bHLH proteins, also known as E-proteins, consist of the three members, E2A (Tcf3), E2-2 (Tcf4), and HEB (Tcf12; Murre, 2005), which bind the E-box (CAN NTG) motif with similar sequence specificity (Fig. S1 A). E-proteins are broadly expressed and heterodimerize with class II bHLH proteins in nonlymphoid cell types. Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al., 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al., 2003;Bayly et al., 2004), as well as the promoter recognition factor TFI ID (Chen et al., 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).E-proteins control different aspects of B cell development (Murre, 2005). E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al.,

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Section: Discussionsupporting

confidence: 55%

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

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“…The E47 transcription factor has been shown to play a crucial role in CSR as it transcriptionally activates the gene for AID (Quong et al, 1999;Sayegh et al, 2003;Sugai et al, 2003), as well as in somatic hypermutation (Michael et al, 2003). We have shown (Frasca et al, 2004a) that splenic B cells from old mice have reduced levels of E47, and subsequently AID, leading to poor CSR and production of secondary isotypes in senescence.…”

Section: Discussionmentioning

confidence: 85%

“…E2A activity has been shown to be necessary for class switching (Quong et al, 1999;Sugai et al, 2003) and the E2A gene, encoding the E47 transcription factor, has been shown to be important in transcriptional regulation of the gene for AID, Aicda (Sayegh et al, 2003). We have shown (Frasca et al, 2004a) that splenic B cells from old mice have reduced levels of E47, and subsequently AID, leading to poor CSR and production of secondary isotypes in senescence.…”

Section: Effects Of Baff On the Transcription Factors That Regulate Cmentioning

confidence: 76%

“…The basic helix-loop-helix transcription factor E47 is crucial for isotype switch and somatic hypermutation (SHM) among peripheral B cells (Quong et al, 1999;Sayegh et al, 2003). In fact, E47 has been shown to be important in transcriptional regulation of the gene for AID, Aicda (Sayegh et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, E47 has been shown to be important in transcriptional regulation of the gene for AID, Aicda (Sayegh et al, 2003). It has been shown that ectopic expression of Id3, which lacks the DNA-binding domain and functions as a dominant negative inhibitor of E proteins, in splenic activated B cells inhibits CSR because of reduced AID transcription (Quong et al, 1999;Sayegh et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

Frasca

Riley

Blomberg

2007

Experimental Gerontology

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The chicken Ig light chain 3′‐enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A

Conlon

Meyer

2005

Eur J Immunol

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Expression of the rearranged chicken immunoglobulin light chain (IgL) gene is regulated by a V gene promoter, a matrix attachment region (MAR) in the J‐C intron and an enhancer downstream of the Ig constant region. Using knockout analysis, we demonstrate that the 3′‐enhancer is not only required for gene activation but is also essential for the maintenance of gene expression. Deletion of the MAR on the other hand increases IgL transcription, indicating that the MAR acts as negative regulator. We demonstrate that Id1 and Id3, dominant‐negative regulators of basic‐region helix‐loop‐helix (bHLH) transcription factors, are able to reduce chicken IgL 3′‐enhancer activity in transient assays and strongly reduce the rate of gene conversion (GC) in DT40 clone 18 cells. Conversely, overexpression of avian E47, a bHLH transcription factor, leads to a dramatic increase in GC rates independent of IgL or activation‐induced cytidine deaminase RNA levels. Thus, E47 is the first transcription factor to activate GC without an apparent increase in transcription.

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E-proteins directly regulate expression of activation-induced deaminase in mature B cells

Cited by 213 publications

References 49 publications

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

The chicken Ig light chain 3′‐enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A

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