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PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

ABSTRACT: PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

PROVIDER: PRJNA550390 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9588760_1.fastq.gz	Fastqsanger.gz
	SRR9588760_2.fastq.gz	Fastqsanger.gz
	SRR9588761_1.fastq.gz	Fastqsanger.gz
	SRR9588761_2.fastq.gz	Fastqsanger.gz
	SRR9588762_1.fastq.gz	Fastqsanger.gz

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PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma.

Project description:Polycomb repressive complex 2 (PRC2) is a chromatin binding complex that represses gene expression by methylating histone H3 at K27 to establish repressed chromatin domains. PRC2 can either regulate genes directly through the methyltransferase activity of its component EZH2 or indirectly by regulating other gene regulators. Gene expression analysis of glioblastoma (GBM) cells lacking EZH2 showed that PRC2 regulates hundreds of interferon-stimulated genes (ISGs). We found that PRC2 directly represses several ISGs and also indirectly activates a distinct set of ISGs. Assessment of EZH2 binding proximal to miRNAs showed that PRC2 directly represses miRNAs encoded in the chromosome 14 imprinted DLK1-DIO3 locus. We found that repression of this locus by PRC2 occurs in immortalized GBM-derived cell lines as well as in primary bulk tumors from GBM and anaplastic astrocytoma patients. Through repression of these miRNAs and several other miRNAs, PRC2 activates a set of ISGs that are targeted by these miRNAs. This PRC2-miRNA-ISG network is likely to be important in regulating gene expression programs in GBM.

| S-EPMC6742368 | biostudies-literature

PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

Project description:Purpose: The goal of this study was to identify genes induced upon type I and II interferon response and how loss of PRC2/EZH2 impacts their induction. Methods: mRNA-seq from cells treated with universal type I IFN alpha/beta or IFN gamma. miRNA-seq from GBM-derived tumor samples.

2019-08-30 | GSE133211 | GEO

PRC2 Inactivation Induces Primary Chemoresistance by Repressing Mitochondrial Apoptosis in T-ALL

Project description:PRC2 Inactivation Induces Primary Chemoresistance by Repressing Mitochondrial Apoptosis in T-ALL

| PRJNA439439 | ENA

PRC2

Project description:PRC2

| PRJNA761389 | ENA

PRC2 Inactivation Induces Primary Chemoresistance by Repressing Mitochondrial Apoptosis in T-ALL

Project description:The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. Here, we report that mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical samples from children with T-ALL treated on recent Dana-Farber Cancer Institute or Children’s Oncology Group clinical trials, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis. In human T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action, including dexamethasone, doxorubicin and vincristine. PRC2 loss induced apoptosis resistance via transcriptional upregulation of the LIM domain transcription factor CRIP2, and subsequent downstream upregulation of the mitochondrial chaperone TRAP1. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation, and pharmacologic inhibition of TRAP1 synergized with dexamethasone and doxorubicin. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention.

2018-10-18 | GSE112147 | GEO

EED226, an allosteric PRC2 inhibitor, modulates gene transcription in EZH2 mutant lymphoma cell Karpas422 through PRC2 inhibition

Project description:Polycomb repressive complex (PRC) 2, containing minimally EZH2, EED and Suz12, is the H3 lysine 27 methyltransferase playing pivotal roles in transcriptional regulation. EZH2 is the catalytic subunit, and H3K27me3 activates PRC2 through binding EED to propagate the repressive mark. Cofactor SAM-competitive (SAM-C) PRC2 inhibitors (PRC2is) have been discovered to treat lymphoma and rhabdoid tumors. Here we report the discovery of EED226, a potent and selective PRC2i directly binding to the H3K27me3 pocket of EED. Upon binding, EED226 induces conformational change in EED protein. Interestingly, it inhibits both the basal and the H3K27me3-stimulated PRC2 activities. Furthermore, EED226 selectively pulled down the endogenous PRC2 complex from human cell lysates, specifically modulates H3K27 methylation and target genes similarly as SAM-C PRC2 inhibitors, and effectively regresses human lymphoma xenograft tumor in mouse. More importantly, EED226 potently inhibits the SAM-C inhibitor-resistant PRC2 and synergizes with SAM-C PRC2i in cell proliferation blocking. Together, EED226 is an inhibitor of PRC2 with a novel mechanism and represent a potential complementary strategy for PRC2-targeted cancer therapy.

2017-01-30 | GSE81267 | GEO

ERK potentiates transactivation and oncogenic function of ERG by phosphorylation induced dissociation of PRC2 complex

Project description:ERK activates ERG-mediated prostate cancer specific gene expression program by phopshorylation induced dissociation of PRC2 complex

2018-02-13 | GSE86232 | GEO

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [nonM]

Project description:In this study, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. Moreover, we find that H3 K27M inhibits PRC2 in trans and can reduce H3K27me3 levels independent of chromatin incorporation. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism.

2020-10-12 | GSE151982 | GEO

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [K27M]

2020-10-12 | GSE151980 | GEO

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [EZHIP]

2020-10-12 | GSE151979 | GEO