Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE26408 | GEO | 2011/02/14
SECONDARY ACCESSION(S): PRJNA136867
REPOSITORIES: GEO
Similar Datasets
Project description:Heirarchical development of B-cells involves the induction and supression of large sets of genes that provide the basis for differentiation and, ultimately, antibody production. We used microarrays to define comprehensive differentiation state-specific transcriptional signatures in order to gain insight into B-cell biology. In addition, we compared profiles of normal B-cells to those of murine lymphoma models that are putatively aligned with different states. B-cells of different differentiation states were purified from the bone marrow and spleen of mice use flow cytometry with antibodies specific for pre-defined markers of each differentiation state. Purified populations were then profiled using Affymetrix Mouse 430A2 gene expression microarrays. Tumors from Bcl6-trangenic mice, Bcl6/Myc dual-transgenic mice and p53/Lig4 double knock-out mice were also profiled using these microarrays in order to assess the similarities/differences between normal and malignant B-cells.
2011-02-14 | E-GEOD-26408 | biostudies-arrayexpress
Project description:We utilized gene expression profiling of a comprehensive panel of purified developmentally defined normal murine B cells to identify unique transcriptional signatures for each subset. To elucidate transcription factor activities that function in a stage-specific fashion, we used gene sets that share transcription factor targets and found that germinal center B cells had a robust enrichment of up-regulated and down-regulated signatures compared with the other B-cell subsets. Notably, we found Yy1 and its targets to be central regulators of the germinal center B (GCB)-specific transcriptional program with binding of Yy1 to select signature genes in GCB cells, and translation of the Yy1 signatures to human GCB cells. We then tested whether our newly generated, stage-specific transcriptional signatures could be used to link murine lymphoma models to stages of normal B-cell development. Although each of the molecularly defined murine lymphoma models conserved certain stage-specific features of normal B-cell development, there was a significant alteration of the normal differentiation signature following malignant transformation. These findings offer important tools and insights for elucidating differences between normal and malignant B cells.
| S-EPMC3041080 | biostudies-literature
Project description:The germinal center (GC) reaction produces high-affinity Abs for a robust adaptive immune response. When dysregulated, the same processes cause GC B cells to become susceptible to lymphomagenesis. It is important to understand how the GC reaction is regulated. In this study, we show that transcription factor YY1 is required to maintain a robust GC reaction in mice. Selective ablation of YY1 significantly decreased in the frequency and number of GC B cells during the GC reaction. This decrease of GC B cells was accompanied by increased apoptosis in these cells. Furthermore, we found that loss of YY1 disrupted the balance between dark zones and light zones, leading to a preferential decrease in dark zone cells. Collectively, these results indicate that YY1 plays an important role in regulating the balance between dark zone and light zone cells in GCs and between survival and death of GC B cells.
| S-EPMC4992619 | biostudies-literature
Project description:YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.
| S-EPMC4863967 | biostudies-literature
Project description:Antibody-mediated immunity is initiated by B cell interactions with cognate antigen, followed by differentiation into multiple cell subsets, including plasmablast, memory, and germinal center (GC) cells. B cell differentiation trajectories are determined by specific transcription factors, yet very few mechanisms that determine B cell fate at the early stage of the response have been described. Here, we report an epigenetic mechanism that specifically suppresses the plasmablast genetic program and promotes GC B cell fate commitment. Single-cell RNA-seq analysis of antigen-specific B cells revealed activated B cell precursors at the pre-GC stage that express high levels of RNA binding proteins, including YTHDF2, which enhances the decay of methylated transcripts. Ythdf2-deficient B cells exhibited intact proliferation and upregulation of early activation markers in response to antigenic stimulation, whereas differentiation into GC B cells was blocked. Mechanistically, B cells required YTHDF2 to attenuate the plasmablast genetic program during GC seeding, and key transcripts of plasmablast-related genes, including Irf4 and Xbp1, were methylated and bound by YTHDF2. Modulation of YTHDF2-dependent gene expression by YTHDF1 and YTHDF3 was less pronounced, and no functional redundancy of these paralogs in GC seeding was observed. Collectively, this study reveals a novel epigenetic mechanism that specifically directs appropriate B cell fate commitment through post-transcriptional suppression of gene expression.
2022-04-24 | GSE189819 | GEO
Project description:OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by ChIP-seq that OBF1 extensively colocalizes with OCT1 and OCT2 and stabilizes their binding. We found that these factors also often colocalize with transcription factors of the ETS family, such as PU.1 and ETS1. Furthermore, we showed that OBF1, OCT2 and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation, such as the master regulators Bcl6 and Foxo1. shRNA knockdown experiments demonstrated that OCT1, OCT2 and OBF1 are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance -such as BCL6- are downregulated, while genes related to exit from the GC program are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived Raji cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls a critical regulatory node in GC differentiation.
2021-02-02 | GSE142039 | GEO
Project description:OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by ChIP-seq that OBF1 extensively colocalizes with OCT1 and OCT2 and stabilizes their binding. We found that these factors also often colocalize with transcription factors of the ETS family, such as PU.1 and ETS1. Furthermore, we showed that OBF1, OCT2 and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation, such as the master regulators Bcl6 and Foxo1. shRNA knockdown experiments demonstrated that OCT1, OCT2 and OBF1 are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance -such as BCL6- are downregulated, while genes related to exit from the GC program are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived Raji cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls a critical regulatory node in GC differentiation.
2021-02-02 | GSE142038 | GEO
Project description:OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by ChIP-seq that OBF1 extensively colocalizes with OCT1 and OCT2 and stabilizes their binding. We found that these factors also often colocalize with transcription factors of the ETS family, such as PU.1 and ETS1. Furthermore, we showed that OBF1, OCT2 and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation, such as the master regulators Bcl6 and Foxo1. shRNA knockdown experiments demonstrated that OCT1, OCT2 and OBF1 are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance -such as BCL6- are downregulated, while genes related to exit from the GC program are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived Raji cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls a critical regulatory node in GC differentiation.
2021-02-02 | GSE142037 | GEO
Project description:OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by ChIP-seq that OBF1 extensively colocalizes with OCT1 and OCT2 and stabilizes their binding. We found that these factors also often colocalize with transcription factors of the ETS family, such as PU.1 and ETS1. Furthermore, we showed that OBF1, OCT2 and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation, such as the master regulators Bcl6 and Foxo1. shRNA knockdown experiments demonstrated that OCT1, OCT2 and OBF1 are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance -such as BCL6- are downregulated, while genes related to exit from the GC program are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived Raji cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls a critical regulatory node in GC differentiation.
2021-02-02 | GSE161840 | GEO
Project description:OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by ChIP-seq that OBF1 extensively colocalizes with OCT1 and OCT2 and stabilizes their binding. We found that these factors also often colocalize with transcription factors of the ETS family, such as PU.1 and ETS1. Furthermore, we showed that OBF1, OCT2 and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation, such as the master regulators Bcl6 and Foxo1. shRNA knockdown experiments demonstrated that OCT1, OCT2 and OBF1 are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance -such as BCL6- are downregulated, while genes related to exit from the GC program are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived Raji cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls a critical regulatory node in GC differentiation.
2021-02-02 | GSE161838 | GEO