Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE79036
PROVIDER: PRJNA314772 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3213590_1.fastq.gz | Fastqsanger.gz | |||
| SRR3213590_2.fastq.gz | Fastqsanger.gz | |||
| SRR3213591_1.fastq.gz | Fastqsanger.gz | |||
| SRR3213591_2.fastq.gz | Fastqsanger.gz | |||
| SRR3213592_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 28 |
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Project description:An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome
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Project description:An oncogenic Ezh2 mutation induces tumors in mice through redistribution of global H3K27 trimethylation
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Project description:The Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is an essential epigenetic modifier able to methylate lysine 27 on histone H3 (H3K27) to induce chromatin compaction, protein complex recruitment and ultimately transcriptional repression. Hematologic malignancies, including Diffuse Large B cell lymphoma (DLBCL) and Acute myeloid leukemia (AML) have shown a high EZH2-mutation frequency (>20%) associated with poor clinical outcomes. Particularly, two distinct oncogenic mutations, so-called gain-of-function (Y641F and A677G) and loss-of-function (H689A and F667I) are found in the catalytic domain of EZH2. In this study, a comprehensive multi-omics approach was employed to characterize downstream effects of H3K27me3 deposition driven by EZH2 mutations. Human embryonic kidney cells (HEK293T) were transfected to generate three stable EZH2 mutants: EZH2(Y641F), EZH2(A677G), and EZH2(H689A/F667I), which were validated via immunoblotting and DIA-MS-based histone profiling assay. The histone profiling assay demonstrated a significant increase of approximately two-fold in H3.1/H3.3K27me3 for Y641F EZH2 mutant. There was a modest increase in the combinatorial PTMs H3.1/H3.3K27me3K36me1 and a significant depletion in H3.1 and H3.3 K27me2. The most depleted peptide was H3.3K27me2K36me2. For the A677G EZH2 mutant, the assay demonstrated an enrichment on H3.1/H3.3K27me3, combinatorial K27me3K36me1 and a slight increase in K27me1 and K18ac but only on H3.1. The most depleted peptide was H3.3K27me2K36me2. The H689A/F667I cell line has the most alterations in global histone PTMs. The most highly enriched were H3.1/H3.3K36me2, H3.1K9me3 and H3.3K36me1. The most depleted modifications were H3.1K23ac and H3.1K27me3.
2023-10-24 | PXD042953 | Pride
Project description:Mutations within the catalytic domain of the histone methyltransferase (HMT) EZH2 have been identified in subsets of Non-Hodgkin Lymphoma (NHL) patients. These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We previously reported the discovery of a potent, selective, S-adenosyl-methionine-competitive and orally bioavailable small molecule inhibitor of EZH2, EPZ-6438. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) led to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of xenograft-bearing mice with EPZ-6438 leads to dose-dependent tumor growth inhibition and eradication of genetically altered NHL with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 day after stopping compound treatment in two EZH2 mutant xenograft models. These data confirm the dependency of mutant NHL on EZH2 activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers. To identify potential biomarker and gain mechanistic insights in EPZ6438 treated lymphoma, lymphoma cell lines with or without EZH2 Y641 mutation were treated with EPZ6438 at Lowest Cytotoxic Concentration (LCC) and 10xLCC. Transcriptomes were profiled on Affemetrix U133 Plus2 chips. Differentially expressed genes and pathways upon compound treatment were anayzed. Lymphoma cell lines WSU-DLCL2, SU-DHL6, Pfeiffer, and Karpas422 were treated by EPZ6438 for 2 days, 4 days and 6 days. Treatment doses are LCC and 10xLCC of each cell lines. KARPAS_422, SUDHL6, and WSU_DLCL2 have the EZH2 Y641 mutation. PFEIFFER does not have the EZH2 Y641 mutation.
2014-02-19 | E-GEOD-49284 | biostudies-arrayexpress
Project description:DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A R882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias. This SuperSeries is composed of the SubSeries listed below.
2016-06-23 | GSE71475 | GEO
Project description:The Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is an essential epigenetic modifier able to methylate lysine 27 on histone H3 (H3K27) to induce chromatin compaction, protein complex recruitment and ultimately transcriptional repression. Hematologic malignancies, including Diffuse Large B cell lymphoma (DLBCL) and Acute myeloid leukemia (AML) have shown a high EZH2-mutation frequency (>20%) associated with poor clinical outcomes. Particularly, two distinct oncogenic mutations, so-called gain-of-function (Y641F and A677G) and loss-of-function (H689A and F667I) are found in the catalytic domain of EZH2. In this study, a comprehensive multi-omics approach was employed to characterize downstream effects of H3K27me3 deposition driven by EZH2 mutations. Human embryonic kidney cells (HEK293T) were transfected to generate three stable EZH2 mutants: EZH2(Y641F), EZH2(A677G), and EZH2(H689A/F667I), which were validated via immunoblotting and DIA-MS-based histone profiling assay. Subsequently, constructs were analyzed under a comprehensive multi-omics approach including label-free whole-cell proteomics, acquired with a Bruker timsTOF Pro HPLC-MS/MS with Ion Mobility. Important protein interactors at nuclear level were dysregulated, such as SMYD3 (SET and MYND domain containing 3), NSD2 (nuclear receptor binding SET domain protein 2) and CHD7 (chromodomain helicase DNA binding protein 7), suggesting a cooperative network of chromatin remodelers for gene expression reprogramming.
2023-10-24 | PXD042875 | Pride
Project description:Enhancer of Zeste Homolog 2 (EZH2) functions as the catalytic component of the Polycomb Repressive Complex 2, a chromatin modifying complex, which mediates methylation of lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark. In cancer, genetic alterations in EZH2 encompass amplifications, deletions and point mutations, and of particular interest are the recurring mutations in the SET domain at tyrosine 641 (Y641). Hematologic malignancies exhibit a prominent association with EZH2Y641 mutations, primarily observed in B cell malignancies such as germinal center diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) with a mutation frequency around 20%. Leukemias and solid tumors like melanoma, prostate, head and neck, sarcomas, and others demonstrate substantially lower EZH2Y641 mutation frequencies. Because the effect of Ezh2Y641F mutations depend on the existing patterns of H3K27 mono-, di-, and tri-methylation, we hypothesized that the oncogenic potential of Ezh2Y641F mutations depends on the developmental stage and cell of origin during which mutations occur. Towards that end, we employed a conditional and inducible mouse model of Ezh2Y641F, crossed with different tissue-specific Cre drivers. We found that heterozygous expression of Ezh2Y641F early in embryonic development, at birth, or in adult hematopoietic stem/progenitor cells resulted in diminished overall survival, which was primarily attributed to hematopoietic defects. Specifically, expression of Ezh2Y641F at the hematopoietic stem cell (HSC) stage did not induce B cell or myeloid transformation, but instead led to bone marrow failure due to both cell intrinsic and cell extrinsic factors. Analysis of gene expression profiles in pro- and pre pro-B cells isolated from the CD19-Cre and Mx1-Cre crosses demonstrated a significant overlap in differentially expressed genes and pathways such as IFN signaling and IL2-Stat5 signaling. Expression of Ezh2Y641F at different times during hematopoietic development also resulted in expression of different pathways in early B cell progenitors, such as E2F targets, heme metabolism and GTPase activity driven by GBP proteins. Forced expression of Gbp2/3 in several lymphoma/leukemia cell lines revealed subtle changes in cell survival, suggesting a possible mechanism for how expression of Ezh2Y641F could have a different effect on hematopoietic transformation depending on when it is expressed. In summary, our study underscores the critical importance of the timing of the Ezh2Y641F mutation in determining its oncogenic activity. The varied temporal contexts result in distinct downstream changes that govern the ultimate oncogenic impact of EZH2 mutations.
2024-11-14 | GSE270480 | GEO
Project description:Mutations or aberrant upregulation of the histone methyltransferase EZH2 occur frequently in human cancers yet EZH2-targeted therapies have only shown very limited clinical benefits in hematological malignancies. We report here that upon EZH2 inhibition, MLL1 interacts with p300/CBP complex that directs H3K27me loss to gain of H3K27ac modification. This histone modification crosstalk leads to transcriptional reprogramming that restricts the therapeutic response to EZH2 inhibition. Concurrent inhibition of H3K27 methylation and acetylation results in transcriptional repression and growth dependency on the MAPK signaling pathway in a large cancer subset. In pre-clinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors or a triple-combination including MAPK inhibition display robust efficacy with tolerable toxicity, in particular in liver and pancreatic cancers. Our results suggest an attractive precision treatment and patient stratification strategy for EZH2-aberrant tumors on the basis of intrinsic MLL1 expression and feedback MAPK activation.
2018-09-10 | PXD010842 |
Project description:As a master regulator of chromatin structure and function, the EZH2 lysine methyltransferase orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non- small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 has proven elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with a new genetically-engineered mouse model of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor that arises from a facile synthesis and possesses improved pharmacologic properties. JQEZ5 promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a defined subset of lung cancer. Gene expression analysis of 7 samples, 3 EZH2 OE tumors, 2 EZH2 OE normal lung samples, and 2 WT lung samples
2015-11-01 | E-GEOD-70046 | 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