EZH2 loss promotes gastric squamous cell carcinoma [CUT&Tag]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069734 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27743542_1.fastq.gz | Fastqsanger.gz | |||
| SRR27743542_2.fastq.gz | Fastqsanger.gz | |||
| SRR27743543_1.fastq.gz | Fastqsanger.gz | |||
| SRR27743543_2.fastq.gz | Fastqsanger.gz | |||
| SRR27743544_1.fastq.gz | Fastqsanger.gz |
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Project description:Gastric Squamous Cell Carcinoma (GSCC) is a rare subtype of gastric cancer with unique histopathology while gastric adenosquamous carcinoma (GASC), which partially shares features of GSCC, is more frequent. Both GSCC and GASC have poor prognosis but the molecular mechanisms underlying these malignancies are unknown. Here, we performed genomics analyses of eleven GSCC samples and found that epigenetic regulation genes were among the most frequently mutated genes. Among them was Enhancer of zeste homolog 2 (EZH2), which was also significantly downregulated in GASC, compared to gastric adenocarcinoma (GAC). Ezh2 loss led to squamous feature both in gastric organoids in vitro and in vivo. Importantly, Ezh2 deficiency, together with Trp53 and Pten loss, both of which were also frequently mutated in GSCC, gave rise to full-blown GSCC in mice. Mechanistically, we found that Ezh2 could repress the expression of Transcription factor AP-2 gamma (Tfap2c), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of Tfap2c reversed Ezh2 loss-driven GSCC into GAC and reduced its resistance to chemo treatment. Our study revealed the mechanisms of GSCC/GASC tumorigenesis and shed light on future treatment.
2025-05-18 | GSE254317 | GEO
Project description:Gastric Squamous Cell Carcinoma (GSCC) is a rare subtype of gastric cancer with unique histopathology while gastric adenosquamous carcinoma (GASC), which partially shares features of GSCC, is more frequent. Both GSCC and GASC have poor prognosis but the molecular mechanisms underlying these malignancies are unknown. Here, we performed genomics analyses of eleven GSCC samples and found that epigenetic regulation genes were among the most frequently mutated genes. Among them was Enhancer of zeste homolog 2 (EZH2), which was also significantly downregulated in GASC, compared to gastric adenocarcinoma (GAC). Ezh2 loss led to squamous feature both in gastric organoids in vitro and in vivo. Importantly, Ezh2 deficiency, together with Trp53 and Pten loss, both of which were also frequently mutated in GSCC, gave rise to full-blown GSCC in mice. Mechanistically, we found that Ezh2 could repress the expression of Transcription factor AP-2 gamma (Tfap2c), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of Tfap2c reversed Ezh2 loss-driven GSCC into GAC and reduced its resistance to chemo treatment. Our study revealed the mechanisms of GSCC/GASC tumorigenesis and shed light on future treatment.
2025-05-18 | GSE254316 | GEO
Project description:EZH2 loss promotes gastric squamous cell carcinoma
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Project description:EZH2 loss promotes gastric squamous cell carcinoma [RNA-seq]
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Project description:To map the chromatin binding sites for SMC1 in OE19 cells, we performed CUT&TAG.
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Project description:To map the chromatin binding sites for various factors in OE19 cells, we performed CUT&TAG.
2023-02-24 | E-MTAB-11356 | biostudies-arrayexpress
Project description:H3K27me3 CUT&Tag analysis of EZH2 mutants in isogenic cell lines
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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. Subsequently, constructs were analyzed under a comprehensive multi-omics approach including: 1) Cleavage Under Targets and Tagmentation (CUT&Tag); 2) chromatin accessibility characterization using the assay for transposase-accessible chromatin with sequencing (ATAC-Seq); 3) transcriptomics (RNA-Seq); 4) label-free whole-cell proteomics, acquired with a Bruker timsTOF Pro HPLC-MS/MS with Ion Mobility, and 5) MS-based untargeted metabolomics, in positive and negative ionization MS/MS mode, acquired with an Agilent 6545 QTOF with a 1290 UHPLC system and HILIC column. Total coverage comprised over 21,000 chromatin regions, 18,000 transcripts, 6,000 proteins and 400 metabolic features. Pair-wise comparison using univariate and supervised multivariate statistical methods revealed significant differences between constructs in each omic level. Furthermore, effector pathway analysis combining omics data revealed distinctive reprogramming effects for each EZH2 mutant.
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Project description:HIF2A(EPAS1) geenome_wide localization by Cut & Tag in MRC5 human fibroblasts ectopically expressing HIF2A in the pBabe vector, and in control MRC5 human fibroblasts containing only the pBabe vector. 2 biological replicates were done for the MRC5-HIF2A cells. Cut & Tag with an anti-H3-K27me3 Ab was done as a positive control for the Cut & Tag experiments.
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