Instructive Role of the Transcription Factor E2A in Early B Lymphopoiesis and Germinal Center B Cell Development

Kwon, Kyong-Rim; Hutter, Caroline; Sun, Qiong; Bilić, Ivan; Cobaleda, César; Malin, Stephen; Busslinger, Meinrad

doi:10.1016/j.immuni.2008.04.014

Cited by 272 publications

(345 citation statements)

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“…These cells remain partially blocked in a myeloid state of differentiation (Kita et al, 1992) and despite the expression of transcription factors PAX5, EBF1 and TCF3 (Figure 1b; Supplementary Figures S2b and c), which are essential for and can promote B-cell differentiation (Seet et al, 2004;Kwon et al, 2008), they do not progress to differentiate into B cells and lack B-cell-specific markers such as CD20 and CD21. We therefore propose that the co-expression of transcription factors acting on plastic chromatin and promoting antagonizing gene expression programs is one of the causes for the developmental limbo characteristic for t(8;21) AML cells.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

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Section: Discussionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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“…We therefore hypothesized that Tcf4 likely compensates for the loss of E2A in late B cell development. To test this hypothesis, we used the Cd23-Cre line, which initiates Cre-mediated deletion in immature B cells of the spleen (Kwon et al, 2008), the floxed Tcf3 allele (Tcf3 fl ), which expresses a nonfunctional E2A-GFP fusion protein upon Cre-mediated elimination of the bHLH domain-encoding exons (Kwon et al, 2008), and the Tcf4 fl allele (Bergqvist et al, 2000). We thus generated Tcf3 fl/fl Tcf4 fl/fl mice (referred to as Tcf3,4 fl/fl or 'WT' mice) and Cd23-Cre Tcf3 fl/fl Tcf4 fl/fl mice (referred to as Cd23-Cre Tcf3,4 fl/fl for the mice and DKO for the respective B cells).…”

Section: Res Ults Efficient Generation Of Mature B Cells Upon Combinementioning

confidence: 99%

“…E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al, 1994;Zhuang et al, 1994). E2A is also essential for V κ -J κ recombination (Inlay et al, 2004) and early B cell development (Kwon et al, 2008). Inactivation of all E-proteins in activated B cells by overexpression of the antagonist ID3 revealed an important role for these transcription factors in promoting CSR to different IgG isotypes (Quong et al, 1999) and activating the Aicda (AID) gene (Sayegh et al, 2003).…”

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confidence: 99%

“…Inactivation of all E-proteins in activated B cells by overexpression of the antagonist ID3 revealed an important role for these transcription factors in promoting CSR to different IgG isotypes (Quong et al, 1999) and activating the Aicda (AID) gene (Sayegh et al, 2003). As shown by conditional Tcf3 inactivation, E2A is largely dispensable for the formation and function of different mature B cell types and plasma cells, except for GC B cell differentiation, which is reduced but not lost in the absence of E2A (Kwon et al, 2008). It is, however, possible that the activity of another E-protein may compensate for the loss of E2A in late B cell differentiation in analogy to the cooperative function of E2A and HEB in T cell development (Jones-Mason et al, 2012).…”

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confidence: 99%

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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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“…E2A is associated with gene expression changes during Bcell development 40 and is essential for the development of pro-, pre-and immature B cells in the bone marrow. 41 To determine if E2A is bound to the CR2/CD21 gene encompassing the DPE in mature B cells, we performed chromatin immunoprecipitation with antibodies specific for the E2A proteins E12 and E47 as well as RNAP as a positive control (Figure 2b). Using Ramos cells, robust enrichment of E12, E47 and RNAP could be detected upstream of the CR2/CD21 TSS (Figure 2b, n52).…”

Section: Transcription Ofmentioning

confidence: 99%

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

et al. 2015

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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.

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Instructive Role of the Transcription Factor E2A in Early B Lymphopoiesis and Germinal Center B Cell Development

Cited by 272 publications

References 48 publications

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

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

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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