Gene expression profiles of H16N2 cells expressing EZH2 variants
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR899421.fastq.gz | Fastqsanger.gz | |||
| ERR899422.fastq.gz | Fastqsanger.gz | |||
| ERR899423.fastq.gz | Fastqsanger.gz | |||
| ERR899424.fastq.gz | Fastqsanger.gz | |||
| ERR899425.fastq.gz | Fastqsanger.gz |
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Project description:A cytosolic role for EZH2 in regulating cell signaling via interaction with the VAV family of proteins has been reported by us previously. However, it is unclear whether EZH2 interactions with VAV are critical for tumorigenesis. Here, we show that cytosolic EZH2 exhibits greater transforming/metastatic capacity than wild-type EZH2 and that targeted disruption of the EZH2-VAV interaction abolishes EZH2-promoted tumorigenesis. We also found that interaction of cytosolic EZH2 with VAV is critical for EZH2-mediated talin methylation and subsequent STAT3 activation. Both cytosolic EZH2 and a methyl-mimicking talin mutant substantially promoted STAT3 activation and tumor growth. We therefore propose that the VAV-dependent cytosolic function of EZH2 may be a critical step in the initiation of cellular transformation, preceding the well-established function of EZH2 in epigenetic silencing of tumor suppressors. Thus, disrupting EZH2-VAV interaction could be an alternative intervention strategy for treatment of cancers associated with EZH2 overexpression.
2017-10-04 | E-MTAB-3599 | biostudies-arrayexpress
Project description:Heterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2encodes the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which mediates mono-, di-, and tri-methylation of histone H3 lysine 27 (H3K27me1/2/3). Most WS-associated EZH2 variants lack functional characterization but are presumed loss of function. However, the lack of early truncating mutations in EZH2 led us to hypothesise a dominant-negative mechanism for WS, which was supported by our structural analysis of all known WS-associated EZH2 variants. We isogenically modelled 10 representative variants in embryonic stem cells and showed they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction. Notably, the pattern of H3K27me2/3 reductions indicated dominant-negative interference on PRC2 activity, even when WS-variants were expressed atlow levels. RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes. Comparative analysis of a gain-of-function EZH2 variant causing growth restriction revealed reciprocal chromatin and transcriptional changes compared to WS-associated variants. Taken together, our findings support a model where EZH2 variants associated with opposing developmental growth syndromes affect not only H3K27me3, but also intergenic H3K27me2, chromatin architecture, and cPRC1 recruitment.
2025-09-03 | GSE302575 | GEO
Project description:Heterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2 encodes the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which mediates mono-, di-, and tri-methylation of histone H3 lysine 27 (H3K27me1/2/3). Most WS-associated EZH2 variants lack functional characterization but are presumed loss of function. However, the lack of early truncating mutations in EZH2 led us to hypothesise a dominant-negative mechanism for WS, which was supported by our structural analysis of all known WS-associated EZH2 variants. We isogenically modelled 10 representative variants in embryonic stem cells and showed they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction. Notably, the pattern of H3K27me2/3 reductions indicated dominant- negative interference on PRC2 activity, even when WS-variants were expressed at low levels. RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes. Comparative analysis of a gain-of-function EZH2 variant causing growth restriction revealed reciprocal chromatin and transcriptional changes compared to WS-associated variants. Taken together, our findings support a model where EZH2 variants associated with opposing developmental growth syndromes affect not only H3K27me3, but also intergenic H3K27me2, chromatin architecture, and cPRC1 recruitment.
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Project description:BMCs from BMT recipient mice transplanted with BMCs-expressing EZH2-mutant were analyzed using Affymetrix GeneChip Mouse430_2 BMCs were extracted from BMT recipient mice transplanted with ABCG2-expressing BMCs and analyzed using Affymetrix GeneChip Mouse430_2
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Project description:Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3). EZH2 expression is significantly upregulated in MPNST. In our study, we investigated the function of EZH2 and the molecular mechanisms that are regulated by EZH2 in MPNST pathogenesis. Our findings enhance the knowledge of EZH2’s function and biology, and have the potential to provide a novel therapeutic approach for MPNST patients in the clinic.
2013-10-28 | GSE46904 | GEO
Project description:Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3). EZH2 expression is significantly upregulated in MPNST. In our study, we investigated the function of EZH2 and the molecular mechanisms that are regulated by EZH2 in MPNST pathogenesis. Our findings enhance the knowledge of EZH2’s function and biology, and have the potential to provide a novel therapeutic approach for MPNST patients in the clinic. An EZH2 knockdown experiment was carried out in MPNST cells. There are one control and one siEZH2 samples for two cell lines (724 and 462) and two repeats for each cell line, so in total there are 8 samples. Two group comparison
2013-10-28 | E-GEOD-46904 | biostudies-arrayexpress
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Project description:CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in cancers and stimulates growth. However, clinically applicable therapeutic strategies based on CARM1 expression in cancer remains to be explored. Here we show that epithelial ovarian cancer is among the cancers with the highest CARM1 amplification rates that predicates a shorter survival. Our unbiased screen show that CARM1-expressing ovarian cancer cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator that silences its target genes. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppressed the growth of CARM1-expressing ovarian tumors in two xenograft models. The observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. CARM1 promotes EZH2 dependent gene silencing by methylating BAF155 to alter the antagonism between EZH2 and BAF155. Together, these results indicate that pharmacological inhibition of EZH2 is a novel therapeutic strategy for CARM1-expressing cancers.
2018-03-02 | GSE95644 | GEO
Project description:CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in cancers and stimulates growth. However, clinically applicable therapeutic strategies based on CARM1 expression in cancer remains to be explored. Here we show that epithelial ovarian cancer is among the cancers with the highest CARM1 amplification rates that predicates a shorter survival. Our unbiased screen show that CARM1-expressing ovarian cancer cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator that silences its target genes. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppressed the growth of CARM1-expressing ovarian tumors in two xenograft models. The observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. CARM1 promotes EZH2 dependent gene silencing by methylating BAF155 to alter the antagonism between EZH2 and BAF155. Together, these results indicate that pharmacological inhibition of EZH2 is a novel therapeutic strategy for CARM1-expressing cancers.
2018-03-02 | GSE95643 | GEO