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

PROVIDER: PRJNA322331 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2454490.fastq.gz	Fastqsanger.gz
	SRR2454491.fastq.gz	Fastqsanger.gz
	SRR2454482.fastq.gz	Fastqsanger.gz
	SRR2454492.fastq.gz	Fastqsanger.gz
	SRR2454483.fastq.gz	Fastqsanger.gz

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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 [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

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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 [ChIP-seq]

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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 [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 [RNA-seq]

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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.

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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

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

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

2016-07-20 | GSE81705 | GEO

CBX8 KO and WT re-expression RNA-seq

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REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR

Project description:Canonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

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CBX8 promotes LUAD growth and metastasis through transcriptional repression of CDKN2C and SCEL

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