Plasmacytic Transcription Factor Blimp-1 Is Repressed by Bach2 in B Cells

Ochiai, Kyoko; Katoh, Yohei; Ikura, Tsuyoshi; Hoshikawa, Yutaka; Noda, Tetsuo; Karasuyama, Hajime; Tashiro, Satoshi; Muto, Akihiko; Igarashi, Kazuhiko

doi:10.1074/jbc.m607592200

Cited by 145 publications

(170 citation statements)

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“…Relative expression the promoter and to the intron of PRDM1 to repress transcription of the gene [40,41], these findings indicate that Bcl6 regulates the expression of PRDM1 through the expression of Bach2. We did not observe any binding of Bcl6 to the MITF gene, suggesting an indirect mechanism for Bcl6-mediated regulation of MITF expression.…”

Section: Relative Expressionmentioning

confidence: 79%

“…As an alternative mechanism, we identified BACH2 as a Bcl6 target gene, which mediates PRDM1 suppression. Bach2 has been shown to repress PRDM1 expression through two different MAREelements, one within the promoter [40] and the other next to the Bcl6 response element 1 (BRE1) within the fifth intron of the PRDM1 gene [41]. Thus, Bcl6 appears to use yet another mechanism to ensure the repressed state of PRDM1 in B cells in addition to the previously described competition for DNA binding with STAT3 [51], inhibition of AP-1 function [26] and direct binding to BRE1 in the PRDM1 gene [23].…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 84%

“…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%

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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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Section: Relative Expressionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 84%

Section: Bcl6 Binds Directly To Bach2 Ung and Irf4mentioning

confidence: 99%

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

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“…Possible candidate cis-elements located in this larger construct could be the binding sites for AP1 TF, which has been reported to increase the promoter activity in the absence of . In addition, a binding site (Maf response element site) for the repressor factor Bach2 that binds to the same site as the AP1 factor has recently been described [21]. However, the most striking finding from our results is the profound stepwise loss of promoter activity of pGL3-(+1/+138) in comparison with a larger construct pGL3-(-123/ +138); therefore one or more important elements must be located within the gap region defined by those constructs.…”

Section: Identification Of Dna Sequences Required For Prdm1 Transcripmentioning

confidence: 99%

Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

et al. 2008

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The positive regulatory domain containing 1, encoded by the PRDM1 gene, is a transcriptional repressor considered as a master regulator that is required and sufficient for plasma cell differentiation. In the present study we have performed sequence analysis of the upstream region of the human PRDM1 gene to detect the minimal promoter region necessary for PRDM1 gene transcription. This region comprises the region upstream of the initiation site, as well as the first exon. Collectively, deletion and mutation analysis in conjunction with luciferase reporter assays, EMSA and supershift assays identified a phylogenetically conserved GC-box as an essential element for PRDM1 expression. This GC-box element matches to a binding site for multiple transcription factors such as SP1 and SP3 isoforms as well as early growth response 1. Chromatin immunoprecipitation assays confirmed the in vivo binding capability of these factors to the human PRDM1 promoter. These studies together characterize for the first time the basal activity of the human PRDM1 promoter, through which several factors, including SP1, SP3 and early growth response 1, modulate its expression through a conserved GC-box.Key words: B cell differentiation Á Human Á PRDM1 Á Transcription factors Supporting Information available online IntroductionPlasma cells (PC), i.e. terminally differentiated B lymphocytes in a post-mitotic state, are immunoglobulin (Ig)-secreting cells playing a central role in the antigen-specific immune response. The plasmacytic differentiation process is regulated by the "turn off" and "turn on" of many specific transcription factors (TF), which are now starting to be elucidated [1][2][3][4]. One of these, the human positive regulatory domain containing 1 with zinc-finger domain (PRDM1), is considered as a key factor that promotes the nonproliferative and differentiated stage of PC [4, 5]. The PRDM1 factor was initially identified as a 98-kDa DNA-binding protein that contains five zinc-finger domains and acts as a repressor of interferon-b gene expression [6]. Its murine homolog, initially called B lymphocyte-induced maturation protein-1 (Blimp-1), was isolated as a mouse gene that is induced during B lymphocyte maturation [7]. It is expressed at high levels only in late B cells and PC, and the ectopic overexpression of PRDM1 is sufficient to drive B lymphocytes to differentiate into PC [7]. Moreover, its expression is required for the formation of Ig-secreting cells [8] and for the maintenance of long-lived PC in bone marrow [9].MYC Here we have defined the minimal promoter for human PRDM1 transcription enclosing a GC-rich element necessary for basal transcription. Moreover, this GC-rich element contains an SP1/early growth response 1 (EGR-1) overlapping binding site to which the regulatory factors SP1, SP3 and EGR-1 can bind, which activate the PRDM1 transcription. Results and discussionStructure of the 5 0 -flanking region and initiation sites of the human PRDM1 gene To obtain insight into the regulation of the human PRDM1 gene and b...

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On the structure‐properties relationship in montmorillonite‐filled polyamide 6 nanocomposites

Motovilin

Denchev

Dencheva

2011

J of Applied Polymer Sci

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Polyamide 6/montmorillonite (MMT) nanocomposites were prepared by melt compounding method comprising 1-7.5 wt % of Nanomer I.24 TL or 5 and 10 wt % of Cloisite 15A organically modified nanoclays. The composite samples were characterized by synchrotron X-ray, thermal and FT-IR spectroscopy methods looking for changes in the micro-and nanostructure of both PA6 matrix and MMT reinforcement as a function of the clay content and type. These data were discussed in conjunction with the mechanical properties of the respective nanocomposites. Generally, the Young's modulus was found to increase proportionally to the clay content being the highest in samples with strong aggregation of MMT at micron length scale. The tensile strength passed through a maximum at 2.5 wt % clay load presenting a homogeneous microstructure with almost no agglomeration. Increasing the amount of MMT produced less crystalline PA6 matrices, richer in c-PA6 polymorph and resulted in larger long spacings of PA6 due to expansion of both crystalline and amorphous domains. V C 2011 Wiley Periodicals, Inc. J Appl Polym Sci 120: [3304][3305][3306][3307][3308][3309][3310][3311][3312][3313][3314][3315] 2011

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Plasmacytic Transcription Factor Blimp-1 Is Repressed by Bach2 in B Cells

Cited by 145 publications

References 45 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

Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

On the structure‐properties relationship in montmorillonite‐filled polyamide 6 nanocomposites

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