JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells

Arguni, Eggi; Arima, Masafumi; Tsuruoka, N; Sakamoto, Akemi; Hatano, Masahiko; Tokuhisa, Takeshi

doi:10.1093/intimm/dxl041

Cited by 81 publications

(70 citation statements)

References 45 publications

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“…Thus, BCL6 autoregulation appears to require neither the lateral groove corepressors nor MTA3/NuRD. One possible explanation is that BCL6 autoregulation works through a competitive mechanism in which mere occupancy of the exon 1 BCL6 binding sites by the BCL6 protein is sufficient to preclude binding by transcription activators such as the STAT proteins (2)…”

Section: Resultsmentioning

confidence: 99%

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mendez¹,

Polo

Yu³

et al. 2008

Molecular and Cellular Biology

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The transcription repressor BCL6 plays an essential role in the formation and function of germinal centers (GCs). While normal B cells promptly shut off BCL6 when they exit the GC, many GC-derived B-cell lymphomas sustain BCL6 expression through chromosomal translocations and activating mutations. We have previously shown that a common effect of lymphoma-associated BCL6 gene alterations is to bypass a negative autoregulatory loop that controls its transcription. In this study, we report that BCL6 autoregulation is independent of several known corepressor complexes including silencing mediator for retinoid and thyroid hormone receptors, nuclear receptor coreceptor, BCL6 corepressor, and MTA3/NuRD. Furthermore, we show that BCL6 can interact with the CtBP (C-terminal binding protein) corepressor both in vitro and in vivo and that CtBP is recruited by BCL6 to its 5 regulatory region. In lymphoma cell lines carrying BCL6 translocations, small interfering RNA-mediated CtBP knock-down selectively relieved the previously silenced wild-type BCL6 allele but not the translocated alleles, which are driven by heterologous promoters. These results demonstrate that CtBP is a novel BCL6 corepressor and suggest that a unique corepressor requirement for BCL6 autoregulation may allow GC B cells to differentially control the expression of BCL6 and other BCL6 target genes in response to environmental stimuli during the GC stage of B cell development.BCL6 is a sequence-specific transcription repressor that is required for the formation of germinal centers (GC), and its deregulated expression underlies development of many GCderived B-cell lymphomas (12,44,47). Expression of BCL6 is developmentally regulated such that in the B-cell lineage, high levels of BCL6 are restricted to the GC stage. GC are dynamic and specialized structures in the secondary lymphoid organs within which B cells undergo immunoglobulin class switch recombination and somatic hypermutation to produce diverse, high-affinity antibodies (17,26). Widely considered to be the master regulator of the GC stage of B-cell development, BCL6 maintains the GC-specific gene expression program by silencing genes involved in B-cell activation (CD69, CD80, and NF-B1), response to DNA damage (TP53 and ATR), cell-cycle regulation (CCND2, CDKN1B, and CDKN1A), and plasma cell differentiation (PRDM1) (25,29,34,37,38,40,41). Thus, neither the memory nor the plasma cell differentiation program can be initiated until expression and activity of BCL6 are extinguished by GC exit signals.BCL6 is a 95-kDa phosphoprotein with six Krüppel-type zinc fingers (ZF) at the C terminus and an N-terminal POZ/BTB domain. Our earlier work demonstrated that the maximum repression activity of BCL6 requires the entire POZ/BTB domain as well as a separate middle region, repression domain II (RDII) (7). To date, a variety of BCL6 corepressors have been described. Among the corepressors with well-documented in vivo functions, nuclear receptor coreceptor (NCoR), silencing mediator for retinoid and thyroid hormon...

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Section: Resultsmentioning

confidence: 99%

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mendez¹,

Polo

Yu³

et al. 2008

Molecular and Cellular Biology

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“…Reverse Transcription-PCR Analysis-Total RNAs were isolated from ES cells with Trizol reagent (Invitrogen) and converted to cDNAs by Superscript III reverse transcriptase (Invitrogen) with oligo(dT) [12][13][14][15][16][17][18] primers (Amersham Biosciences). PCR products were subjected to 1.5% agarose electrophoresis gel.…”

Section: Methodsmentioning

confidence: 99%

“…These results suggest that the binding sites for STAT3 and Oct-3/4 are located in Ϫ2600/Ϫ2220 and Ϫ2220/Ϫ1400, respectively. Based on several target sequences of STAT3 that have been reported (17,18,19), the consensus binding sequence of STAT3 seems to be 5Ј-TTC(C/T)N(A/G)GAA-3Ј, where N represents any nucleotide. When we looked for this sequence in Ϫ2600/Ϫ2220, one similar sequence (5Ј-TTCTGATAA-3Ј) was found at Ϫ2235/ Ϫ2227.…”

Section: Stat3 and Oct-3/4 Directly Bind To The Promoter Region Of Eementioning

confidence: 99%

STAT3 and Oct-3/4 Control Histone Modification through Induction of Eed in Embryonic Stem Cells

Ura

Usuda

Kinoshita

et al. 2008

Journal of Biological Chemistry

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Mouse embryonic stem (ES) cells can self-renew in the presence of leukemia inhibitory factor (LIF). Several essential transcription factors have been identified for the self-renewal of mouse ES cells, including STAT3, Oct-3/4, and Nanog. The molecular mechanism of ES cell self-renewal, however, is not fully understood. In the present study, we identified Eed, a core component of Polycomb repressive complex 2, as a downstream molecule of STAT3 and Oct-3/4. Artificial activation of STAT3 resulted in increased expression of Eed, whereas expression of a dominant negative mutant of STAT3 or suppression of Oct-3/4 expression led to down-regulation of Eed. Reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that STAT3 and Oct-3/4 directly bind to the promoter region of Eed, suggesting that Eed is a common target molecule of STAT3 and Oct-3/4. We also found that suppression of STAT3, Oct-3/4, or Eed causes induction of differentiation-associated genes as well as loss of Lys 27 -trimethylated histone H3 at the promoter regions of the differentiation-associated genes. Suppression of STAT3 and Oct-3/4 also resulted in the absence of Eed at the promoter regions. These results suggest that STAT3 and Oct-3/4 maintain silencing of differentiation-associated genes through up-regulation of Eed in self-renewing ES cells. Embryonic stem (ES)5 cells are derived from the inner cell mass of the mammalian blastocyst and have two major characteristics, pluripotency and self-renewal (1, 2). Previous studies have identified several essential transcription factors for the self-renewal of mouse ES cells, such as Oct-3/4, Nanog, and STAT3 (3). Oct-3/4 is a POU-family transcription factor involved in inner cell mass formation (4). A precise level of Oct-3/4 expression is required for maintenance of ES cells: repression of Oct-3/4 leads to trophectodermal differentiation, and overexpression of Oct-3/4 stimulates differentiation, mainly to extraembryonic endoderm (5). Nanog is a homeodomain transcription factor whose overexpression sustains ES cell self-renewal (6). Targeted disruption of the nanog gene results in ES cell differentiation, primarily along the primitive endoderm lineage, suggesting that Nanog prevents ES cells from endoderm differentiation (7).The pluripotency and self-renewal of mouse ES cells can be maintained by the presence of leukemia inhibitory factor (LIF). LIF stimulation leads to the activation of transcription factor STAT3. Previously, using a fusion protein consisting of STAT3 and the ligand-binding domain of estrogen receptor (STAT3ER), we demonstrated that the self-renewal of ES cells can be maintained by activation of STAT3ER with a synthetic estrogen receptor ligand, 4-hydroxytamoxifen (4HT), even in the absence of LIF (8). Another study showed that expression of a dominant negative mutant of STAT3 causes differentiation of ES cells (9). These observations indicate that the activation of STAT3 is essential and sufficient for the self-renewal of mouse ES cells.Despite having ...

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“…Thus, Bcl6 acetylation preferentially abrogates its ability to functionally associate with the corepressor MTA3. There has been some evidence of competition between Bcl6 and STATs at cis-regulatory elements, including the Prdm1 gene locus (29,30). Prdm1 expression is driven by STAT5 in CD4 T cells (9,31).…”

Section: Significancementioning

confidence: 99%

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

Nance

Bélanger

Johnston

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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T follicular helper (Tfh) cells are essential providers of help to B cells. The transcription factor B-cell CLL/lymphoma 6 (Bcl6) is a lineage-defining regulator of Tfh cells and germinal center B cells. In B cells, Bcl6 has the potential to recruit distinct transcriptional corepressors through its BTB domain or its poorly characterized middle domain (also known as RDII), but in Tfh cells the roles of the Bcl6 middle domain have yet to be clarified. Mimicked acetylation of the Bcl6 middle domain (K379Q) in CD4 T cells results in significant reductions in Tfh differentiation in vivo. Blimp1 (Prdm1) is a potent inhibitor of Tfh cell differentiation. Although Bcl6 K379Q still bound to the Prdm1 cis-regulatory elements in Tfh cells, Prdm1 expression was derepressed. This was a result of the failure of Bcl6 K379Q to recruit metastasis-associated protein 3 (MTA3). The loss of Bcl6 function in Bcl6 K379Q-expressing CD4 T cells could be partially rescued by abrogating Prdm1 expression. In addition to Prdm1, we found that Bcl6 recruits MTA3 to multiple genes involved in Tfh cell biology, including genes important for cell migration, cell survival, and alternative differentiation pathways. Thus, Bcl6 middle domain mediated repression is a major mechanism of action by which Bcl6 controls CD4 T-cell fate and function.

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JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells

Cited by 81 publications

References 45 publications

CtBP Is an Essential Corepressor for BCL6 Autoregulation

CtBP Is an Essential Corepressor for BCL6 Autoregulation

STAT3 and Oct-3/4 Control Histone Modification through Induction of Eed in Embryonic Stem Cells

Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3

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