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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. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Matt Teater

PROVIDER: E-GEOD-81705 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 [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 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

Project description:The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. RNA sequencing and H3K27me3 ChIP sequencing of human DLBCL cell lines and murine BCL1 cell line. RNA sequencing, H3K27me3 and H3K4me3 ChIP sequencing of B cells from de-identified human tonsills.

2013-05-13 | E-GEOD-45982 | biostudies-arrayexpress

DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID

Project description:Changes in DNA methylation are required for the formation of germinal centers (GC), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated recently in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCB) isolated from wild type (WT) and AID-deficient (Aicda-/-) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda-/- animals. Differentially methylated cytosines (DMCs) between GCB and naïve B cells (NB) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells. ERRBS and RNA-seq of wild type and Aicda knockout murine naive and germinal center B cells. ERRBS of human naive and germinal center B cells

2015-09-15 | E-GEOD-71702 | biostudies-arrayexpress

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Single Cell RNA-Seq)

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2016-03-27 | E-GEOD-77847 | biostudies-arrayexpress

H3K4me2 and gene expression profiling in control and KMT2D KD murine B220 cells

Project description:Define and compare H3K4me2 enrichment in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Compare gene expression by RNAseq in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Using H3K4me1/2 ChIPseq and RNAseq we profiled murine B220 purified cells from tumors transduced with EV (n=3) or KMT2D-shRNA (n=3).

2015-08-28 | E-GEOD-67291 | biostudies-arrayexpress

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia

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

2016-03-27 | E-GEOD-77849 | biostudies-arrayexpress

Transcriptome profiling of post-mature green seeds from Arabidopsis ddcc mutant and wild-type

Project description:The role of on-CG methylation in seed development and dormancy remains unknown. There are four genes in charge of non-CG methylation in Arabidopsis: drm1, drm2, cmt2 and cmt3. The majority of non-CG methylation in vegetative tissues, leaf, is gone in homozygous ddcc mutant line (Hume et al., 2014). To uncover the possible role of non-CG DNA methylation in seed development and dormancy, we characterized the transcriptome of ddcc mutant in Arabidopsis post-mature green seeds using Illumina sequencing. Meanwhile, post-mature green seeds from wild type were used as control. Illumina sequencing of transcripts from post-mature green seeds of ddcc mutant and wild type. Two biological replicates were collected.

2016-07-03 | E-GEOD-76447 | biostudies-arrayexpress

Sox10 regulates stem/progenitor and mesenchymal cell states in mammary epithelial cells

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

2015-08-04 | E-GEOD-71300 | biostudies-arrayexpress

Expression profiling of fetal mammary cells

Project description:We use RNA-sequencing to generate gene expression profiles of fetal mammary cells with unique sorting strategies. These analyses reveal that sorting fetal mammary cells with Sox10 and EpCAM sorting markers provides a stroma-free fMaSC-enriched cell population. The gene expression profiling of these cells offers a resources to probe the molecular mechanisms that specify this unique cell state. Examination of 2 different sorting strategies for fetal mammary cells

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