Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch

Muto, Akihiko; Ochiai, Kyoko; Kimura, Yoshitaka; Itoh-Nakadai, Ari; Calame, Kathryn; Ikebe, Dai; Tashiro, Satoshi; Igarashi, Kazuhiko

doi:10.1038/emboj.2010.257

Cited by 164 publications

(197 citation statements)

References 42 publications

(88 reference statements)

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“…Whereas Pax5 seems to promote AICDA expression [4,61], Bcl6 binds directly to UNG and is needed for its expression. Here, we show that Bcl6 is not only the direct repressor of PRDM1, but also directly maintains the expression of BACH2, which represses PRDM1 expression [40][41][42]. Also, the expression of MITF was dependent on Bcl6, but the exact mechanism remains unclear.…”

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confidence: 83%

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Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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confidence: 83%

“…3), raising a possibility that the prominent mechanism by which Bcl6 regulates PRDM1 is not through direct DNA binding. Therefore, we searched for other Bcl6 regulated genes that have been reported to regulate PRDM1 or plasma cell differentiation, such as BACH2 [40][41][42], MITF [43], IRF4 [44,45].…”

Section: Bcl6 Binds Directly To Bach2 Ung and Irf4mentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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“…Based on the finding that Bach2-deficient mice have fewer class-switched B cells [9] and that miR-148a targets Bach2 (Fig. 3D), premature expression of miR-148a should be accompanied with a reduction in the frequency of class-switched B cells.…”

Section: Ectopic Mir-148a Enhances Irf4 and Blimp-1 Expression And Prmentioning

confidence: 99%

“…During a GC reaction, Pax5 and IRF4 cooperate to produce activation-induced cytidine deaminase (AID), a DNA mutator required for somatic hypermutation and CSR [6]. In addition, Bcl6 serves to maintain a centroblast in the cell cycle despite the presence of DNA damage introduced by AID [7], and Bach2 [8,9] and Mitf [10] delay the premature differentiation of a GC B cell into a plasmablast by repressing the PC regulator Blimp-1 and preventing further upregulation of IRF4, respectively [10,11], thereby increasing the time window for affinity maturation and CSR. In support of these roles, Bach2-and Mitf-deficient B cells differentiate more rapidly into PCs, resulting in fewer classswitched B cells and increased amounts of antigen-specific serum IgM [8,10].…”

Section: Introductionmentioning

confidence: 99%

“…Compared to the results obtained in the experiments with prematurely expressed miR-148a, the knockdown approach revealed, as expected, the opposite effect: a small but significant reduction in the frequency of CD138 + B cells and IgM secretion following miR-148a knockdown (Supporting Information Figs. 6-8).Based on the finding that Bach2-deficient mice have fewer class-switched B cells [9] and that miR-148a targets Bach2 (Fig. 3D), premature expression of miR-148a should be accompanied with a reduction in the frequency of class-switched B cells.…”

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miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into longlived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitfare essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1 + cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.Keywords: B cells r Blimp-1 r MicroRNAs r miR-148a r Plasma cell differentiation r Bach2, Mitf See accompanying article by Haftmann et al.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe generation of antibody-secreting plasma cells (PCs) and memory B cells is essential for eliminating pathogens and establishing Correspondence: Prof. Hans-Martin Jäck e-mail: hjaeck@molmed.uni-erlangen.de effective protection after vaccination. After antigen encounter, B cells are clonally expanded in the T-cell zone of a peripheral lymphatic organ and differentiate quickly into IgM-secreting short-lived PCs (extrafollicular pathway). If an antigen-activated * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1206-1215 Molecular immunology 1207B cell receives T-cell help, some of these cells move from the Tcell zone to a B-cell follicle located in the B-cell zone. There, they are further expanded, resulting in the formation of a germinal center (GC). During a GC reaction, B cells undergo somatic hypermutation (SHM) of their immunoglobulin variable region exons and class switch recombination (CSR). After B cells with highaffinity and class-switched antigen receptors have been selected, they leave the GC and differentiate either into memory B cells or long-lived PCs [1][2][3]. The differentiation of mature B cells into long-lived PCs via the GC pathway is tightly controlled by a regulatory network of mutually exclusive transcription factors; one set maintains the GC reaction, and the other is re...

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The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation

Ruan

Chen

et al. 2023

FEBS Letters

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Naïve B cells become activated and differentiate into antibody‐secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain‐containing adapter protein with coiled‐coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell‐specific Wac knockout mice have severely compromised T cell‐dependent and ‐independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac‐deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac‐mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.

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Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch

Cited by 164 publications

References 42 publications

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation

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