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EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81705 | GEO | 2016/07/20

SECONDARY ACCESSION(S): PRJNA322331

REPOSITORIES: GEO

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EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis.

Project description:The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

| S-EPMC5000552 | biostudies-literature

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-20 | E-GEOD-81705 | biostudies-arrayexpress

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis [RNA-seq]

Project description:EZH2 mediates the humoral immune response and drives lymphomagenesis through de novo formation of bivalent chromatin domains and critical germinal center (GC) B cell promoters. We show that such formation is dependent on the presense of BCL6 and the presence of non-canonical PRC1-BCOR complex. We observe that BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in vitro, in vivo, and in primary human DLBCLs. DLBCL cell lines treated with BCL6 inhibitor 79-6.1085

2016-07-20 | E-GEOD-73109 | biostudies-arrayexpress

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis [ChIP-seq]

Project description:The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through de novo formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions EZH2 in driving GC formation and lymphoma precursor lesions are dependent on the presence of the BCL6 transcriptional repressor, both of which are in turn dependent on the presence of non-canonical PRC1-BCOR complex. BCL6-BCOR complexes assemble preferentially at bivalent promoters in an H3K27me3-dependent manner. We observe specific induction of the CBX8 chromodomain protein in GC B cells. CBX8 binds to H3K27me3 at bivalent promoters and is required for stable association of BCOR complex and its histone modifications. CBX8 loss of function in B cells phenocopies loss of EZH2 and H3K27me3. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in vitro, in vivo and in primary human DLBCLs. KDM2B ChIP-sequencing of OCI-Ly1 cells

2016-07-20 | E-GEOD-81623 | biostudies-arrayexpress

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis [ChIP-seq]

2016-07-20 | GSE81623 | GEO

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis [RNA-seq]

2016-07-20 | GSE73109 | GEO

EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis

Project description:EZH2 and BCL6 cooperate to assemble CBX8-BCOR Polycomb complex to repress bivalent promoters, mediate germinal center formation and promote lymphomagenesis

| PRJNA322331 | ENA

Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis.

Project description:Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with failure to repress immune synapse genes linked to GC exit, which are also direct targets of the transcriptional repressor BCL6. We found that BCL6 directly binds LSD1 and recruits it primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of BCL6 and significantly delayed BCL6-driven lymphomagenesis. Administration of catalytic inhibitors of LSD1 had little effect on GC formation or GC-derived lymphoma cells. Using a CRISPR-Cas9 domain screen, we found instead that the LSD1 Tower domain was critical for dependence on LSD1 in GC-derived B cells. These results indicate an essential role for LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6.

| S-EPMC6294324 | biostudies-literature

Histone demethylase LSD1 is required for germinal center formation and BCL6 driven lymphomagenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-10 | GSE118783 | GEO

Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.

Project description:Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte-induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.

| S-EPMC3859423 | biostudies-literature

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