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Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

ABSTRACT: The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein we show that while GC formation is only minimally impaired in Bcl6+/- or Bach2+/- mice, double heterozygous Bcl6+/-Bach2+/- mice exhibit profound reduction in GC formation. Splenic B-cells from Bcl6+/- Bach2+/- mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1 and CD138. ChIP-seq revealed that in B-cells BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6 including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B-cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47784 | GEO | 2013/11/17

SECONDARY ACCESSION(S): PRJNA207804

REPOSITORIES: GEO

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Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Project description:The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein we show that while GC formation is only minimally impaired in Bcl6+/- or Bach2+/- mice, double heterozygous Bcl6+/-Bach2+/- mice exhibit profound reduction in GC formation. Splenic B-cells from Bcl6+/- Bach2+/- mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1 and CD138. ChIP-seq revealed that in B-cells BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6 including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B-cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation. ChIP-seq using P18 antibodies in OCI-Ly7 cells

2013-11-17 | E-GEOD-47784 | biostudies-arrayexpress

Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision

Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.

2021-07-18 | GSE180277 | GEO

Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision II

2022-06-08 | GSE180460 | GEO

Effect of Bach2 overexpression in BCL6+/+ and -/- BCR-ABL1 transformed pre-B cells

Project description:The aim was to investigate how BCL6 genotype affects Bach2 dependent gene expression changes. We compared gene expression profiles of BCL6+/+ and BCL6-/- BCR-ABL1 transformed pre-B cells after inducible overexpression of Bach2.

2013-07-11 | E-GEOD-41042 | biostudies-arrayexpress

BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.

Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells

2013-06-27 | E-GEOD-44420 | biostudies-arrayexpress

Bach2 regulates B cell survival to maintain germinal centers and promote B cell memory

Project description:The transcription factor Bach2 serves as a crucial regulator of the germinal center (GC) reaction, which is required for production of high-affinity antibodies and establishment of long-lived B cell memory. However, the stage at which Bach2 controls the GC programs and the precise mechanism underlying these processes remain poorly understood. In this study, we show that genetic ablation of Bach2 in GC B cells of mice impairs their survival and maintenance, and memory B cell formation. These defects can be rescued by enforced expression of anti-apoptotic gene Bcl2. As expected, Bach2-deficient GC B cells are defective in antibody affinity maturation, but have normal somatic hyper mutation and class switch recombination of immunoglobulin genes. Mechanistically, Bach2 controls the GC programs by directly repressing pro-apoptotic gene Bim and a set of genes involved in cell stress response and metabolic processes. Thus, our work reveals the precise roles of Bach2 in the GC biology, and demonstrates that Bach2 acts as a crucial survival regulator of GC B cells, providing a key mechanism underlying GC B maintenance and B cell memory formation.

2022-06-05 | GSE205400 | GEO

Effect of Bach2 overexpression in BCL6+/+ and -/- BCR-ABL1 transformed pre-B cells

Project description:The aim was to investigate how BCL6 genotype affects Bach2 dependent gene expression changes.

2013-07-11 | GSE41042 | GEO

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

2022-09-02 | PXD036457 | Pride

BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.

2013-06-27 | GSE44420 | GEO

BLIMP-1 is insufficient to induce antibody secretion in the absence of IRF4

Project description:Differentiation of B cells into antibody secreting cells (ASCs), plasmablasts and plasma cells, is regulated by a network of transcription factors. Within this network factors including PAX5 and BCL6 prevent ASC differentiation and maintain the B cell phenotype whereas BLIMP-1 and high IRF4 expression promote plasmacytic differentiation. BLIMP-1 is thought to induce immunoglobulin secretion. While IRF4 is needed for the survival of ASCs, its role in the regulation of antibody secretion has been controversial. BCL6-deficient DT40 B cell line has upregulated BLIMP-1 expression and secrete antibodies. In order to study the role of IRF4 in regulation of antibody secretion we have created a double knockout (DKO) DT40 B cell line deficient in both IRF4 and BCL6. This DKO cell line did not upregulate PRDM1 (the gene encoding for BLIMP-1) expression or secrete IgM. Even enforced BLIMP-1 expression in DKO cells or IRF4-deficient cells could not induce IgM secretion while it did in WT cells. However, enforced IRF4 expression in DKO cells induced strong IgM secretion. Our findings support a model where IRF4 expression in addition to BLIMP-1 expression is required to induce antibody secretion.

2018-03-05 | GSE94836 | GEO

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