Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma
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PROVIDER: PRJNA998470 | ENA |
REPOSITORIES: ENA
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Project description:Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma (CUT&Run)
| PRJNA1139185 | ENA
Project description:Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations, alone or in combination, on the epigenetic landscape, we applied a single cell approach, based on Cytometry by Time of Flight (CyTOF), to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is dominant over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present analysis to reveal potential cross talk between various modifications in the epigenetic network, validated by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells
2024-12-31 | GSE238258 | GEO
Project description:Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations, alone or in combination, on the epigenetic landscape, we applied a single cell approach, based on Cytometry by Time of Flight (CyTOF), to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is dominant over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present analysis to reveal potential cross talk between various modifications in the epigenetic network, validated by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells
2025-01-31 | GSE272889 | GEO
Project description:Epigenetic alterations have been increasingly implicated in oncogenesis. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. Mouse Embryonic Fibroblasts (MEFs) conditionally inactivated for Ezh2, Snf5 and Ezh2, or from control WT MEFs were used to evaluated epigenetic antagonism between Snf5 and Ezh2 in the control of gene expression programs. Snf5-deficient lymphoma samples and control CD8+ WT T-cells were used to evaluate genetic programs misregulated by Snf5 inactivation during tumorigenesis. RNA was isolated from each of these samples and used for gene expression profiling on Affymetrix arrays.
2010-10-19 | E-GEOD-23656 | biostudies-arrayexpress
Project description:Chromatin modifications are increasingly recognized as a key mechanism in cancer. The histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) is the enzymatic subunit of the polycomb PRC2 complex and methylates histone H3K27, thereby, mediating gene silencing. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation, tumor development and metastasis in a respective mouse model. Further microarray analysis of EZH2 knock down, or functionally linked HDAC-inhibitor treatment revealed an undifferentiated reversible phenotype in ET maintained by EZH2. EZH2 suppression resulted in a generalized loss of H3K27me3 as well as an increase in H3 acetylation levels. In addition, ChIP-Chip assays for H3K27me3 identified genes that had specifically lost H3K27me3 upon EZH2 silencing. These findings suggested that stemness features are preserved via epigenetic mechanisms. Taken together, the genetic EWS-Fli1 translocation is intimately linked to global and gene specific epigenetic alterations in ET biology. EZH2 mediates neuroectodermal and endothelial embryonal tumor stem cell growth and metastasic spread induced by a translocation derived chimeric transcription factor. Keywords: PNET, Ewing Tumor Epigenetic regulation A673 transiently transfected with siRNA-EZH2 and siRNA-scrambled were harvested and Chromatin-IPs of H3K27me3 or H3 followed by microarray hybridisation were carried out. For detailed procedures see Burdach et al. Epigenetic Maintenance of Stemness and Malignancy in Peripheral Neuroectodermal Tumors by EZH2.
2010-05-18 | E-GEOD-15890 | biostudies-arrayexpress
Project description:Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry (MS) analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. Interestingly, FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme which deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to Bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor Bortezomib response.
2019-08-26 | PXD015008 | Pride
Project description:Targeting EZH2 increases the vulnerability of triple-negative breast cancer
| PRJNA445854 | ENA
Project description:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome ChIP-seq for EZH2 in two cell types
2014-09-01 | E-GEOD-57632 | biostudies-arrayexpress
Project description:The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. With a single LPS stimulation, Ezh2 null(Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.
2023-07-20 | PXD041265 | Pride
Project description:We used EZH2i-targeted hematological malignancies as an examples and focused on molecular characterization of EZH2 Y641 mutant hematological cell lines. We used the proteomic strategies and compared the protein expression level and lysine methylation level (including mono-, di-, and trimethylaiton) in EZH2 wild-type (EZH2 WT), EZH2 Y641N and Y641F (EZH2 MUT) cell lines.
2019-12-17 | PXD016779 |