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

Abstract

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.,

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

“…3C). This defect was not surprising as E2A has been shown to be critical for both the growth of several Burkitt Lymphoma lines as well as a critical TF in GC B cells . Since the accumulation of mutations might be linked to cell division, it is possible that some or all of the SHM defects in the clone are explained by decreases in proliferation.…”

“…Here, we show that transcription factor binding at these DIVAC elements correlates with targeting of SHM in the context of an SHM reporter assay. Using a proteomics approach, we uncovered numerous factors that interact biochemically with DIVAC elements—with a number of them, including E2A, MEF2B, and members of the Ikaros family reported to be involved in B cell development or GC B cell function .…”

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

“…The observation of either loss-of-function mutations in Id3 or gain of function of E2A in Burkitt's lymphoma validates Id3's role as a tumor suppressor. Physiologically, E2A mediates germinal center B cell survival and function through critical genes, while the upregulation of Id proteins keeps their activity in check [63,117]. In the case of BL, the lack of E2A inhibition by mutated Id3 perpetrates a tonic BCR and PI3K signaling that drives GC B cellderived lymphomagenesis.…”

YY1 binds to the E3ʹ enhancer and inhibits the expression of the immunoglobulin κ gene via epigenetic modifications

“…S2). 23 A previous study showed that E2A binds to multiple regulatory elements across the human Igj gene, including E3ʹ. 23 A previous study showed that E2A binds to multiple regulatory elements across the human Igj gene, including E3ʹ.…”

“…2018 John Wiley & Sons Ltd, Immunology, 155, 491-498(encoded by the TCF4 gene) are essential for both GC Bcell and plasma cell development and that the levels of E2A remain high at both stages of B-cell development 23. …”