MTA3 and the Mi-2/NuRD Complex Regulate Cell Fate during B Lymphocyte Differentiation

Fujita, Naoyuki; Jaye, David L.; Geigerman, Cissy; Akyildiz, Adil; Mooney, Myesha R.; Boss, Jeremy M.; Wade, Paul A.

doi:10.1016/j.cell.2004.09.014

Cited by 292 publications

(315 citation statements)

References 51 publications

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“…BCL6 is not expressed in terminally differentiated plasma cells; however, forced expression of BCL6 in plasma cells causes a loss of terminal differentiation markers and reversion to a less differentiated state. By contrast, downregulation of BCL6 by RNA interference causes mature B-cells to express plasma cell markers (Fujita et al, 2004). These data suggest that BCL6 is a master regulator of B-cell differentiation.…”

Section: Introductionmentioning

confidence: 87%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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Section: Introductionmentioning

confidence: 87%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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“…27 Co-staining utilized rabbit anti-cytoBD-CA-2 (1:200) and mouse anti-BDCA-2 (1:10). Bound antibodies were detected with anti-rabbit IgG Alexa-568 and anti-mouse IgG Alexa-488.…”

Section: Immunostainingmentioning

confidence: 99%

“…Sections were mounted and cover slipped for viewing by immunofluorescence confocal microscopy using a Â 63 objective as detailed previously. 25,27 For immunohistochemical analysis, formalinfixed, paraffin-embedded tissue sections underwent deparaffinization and rehydration followed by antigen unmasking in 100 mM Tris buffer, pH 10. 28 For single antibody labeling experiments, after blocking, primary antibodies, including anti-cyto BDCA-2 (1:50), anti-CD123 (1:300), and anti-CD3 (1:5), were separately applied.…”

Section: Immunostainingmentioning

confidence: 99%

Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms

et al. 2006

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“…Bcl6 also represses genes that are involved in B-cell activation and in B-cell-T-cell interactions [17][18][19]. Importantly, several experiments have proposed a double-negative regulatory circuit between Bcl6 and Blimp-1 [18,[20][21][22][23][24]. PRDM1 (encoding Blimp-1) is directly repressed by Bcl6 in B cells [23,24] and, in contrast, enforced Blimp-1 expression in B cells is shown to downregulate the BCL6 gene [4,25].…”

Section: Introductionmentioning

confidence: 99%

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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MTA3 and the Mi-2/NuRD Complex Regulate Cell Fate during B Lymphocyte Differentiation

Cited by 292 publications

References 51 publications

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms

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

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