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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]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81623 | GEO | 2016/07/20

SECONDARY ACCESSION(S): PRJNA322333

REPOSITORIES: GEO

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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.

Dataset Information

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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