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An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome

ABSTRACT: An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome

OTHER RELATED OMICS DATASETS IN: GSE79036

PROVIDER: PRJNA314766 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3213590_1.fastq.gz	Fastqsanger.gz
	SRR3213590_2.fastq.gz	Fastqsanger.gz
	SRR3213620.fastq.gz	Fastqsanger.gz
	SRR3213630.fastq.gz	Fastqsanger.gz
	SRR3213591_1.fastq.gz	Fastqsanger.gz

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An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome [RNA-seq]

Project description:B-cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase, but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic EZH2 gain-of-function mutation (Y646F in human, Y641F in the mouse) can be conditionally expressed. Expression of Ezh2Y641F in mouse B-cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Bcl2 overexpression or p53 loss, but not c-Myc overexpression, further accelerated lymphoma progression, and expression of mutant B-Raf but not mutant N-Ras further accelerated melanoma progression. Although expression of Ezh2Y641F increased abundance of global H3K27 trimethylation (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 associated with increased transcription at many loci. These results suggest that Ezh2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure inducing both repression and activation of polycomb-regulated loci. B cells: 4 WT vs 4 Y641F samples, Melanoma: WT (480, 855) vs Y641F (480D, 855D) isogenic cell lines differing only for the presence of WT vs Y641F Ezh2.

2016-05-13 | E-GEOD-79035 | biostudies-arrayexpress

An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome [RNA-seq]

2016-05-13 | GSE79035 | GEO

An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome

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

2016-05-02 | GSE79036 | GEO

Mus musculus

Project description:An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27m3 through the genome [RNA-seq]

| PRJNA314772 | ENA

Truncated BRPF1 cooperates with Smoothened to induce adult Shh medulloblastoma

Project description:Truncated BRPF1 cooperates with Smoothened to induce adult Shh medulloblastoma

| PRJNA525143 | ENA

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

Cre-recombinase expression cooperates with FLT3ITD/ITD to induce acute myeloid leukemia

Project description:Cre-recombinase expression cooperates with FLT3ITD/ITD to induce acute myeloid leukemia

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Inhibition of the epigenetic regulator Ezh2 redistributes bivalent domains within transcriptional regulators associated with Wnt and Hedgehog pathways

Project description:Inhibition of the epigenetic regulator Ezh2 redistributes bivalent domains within transcriptional regulators associated with Wnt and Hedgehog pathways

| PRJNA805533 | ENA

Bottom-up proteomics of EZH2 mutants in isogenic cells

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

Histone PTM profiling analysis of EZH2 mutants in isogenic cells

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

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