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Genome-wide chromatin accessibility change after PRC2 inhibition by MAK683 treatment

ABSTRACT: Genome-wide chromatin accessibility change after PRC2 inhibition by MAK683 treatment

PROVIDER: PRJNA761397 | ENA |

REPOSITORIES: ENA

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Genome-wide chromatin accessibility change after PRC2 inhibition by MAK683 treatment

Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that multiple senescence-associated secretory phenotype (SASP) genes, such as Gata4, Mmp2/10, Itga2 and Gbp1, are derepressed upon PRC2 inhibition and contribute to decreased Ki67+, ECM reorganization, inflammation and tumor regression even in Cdkn2a/p16 knockout tumor.

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The chromatin accessibility change by PRC2 inactivation with or without IFNγ stimulation in human MPNST cancer cells

Project description:PRC2-isogenic human malignant peripheral nerve sheath tumor (MPNST) M3 cells were generated through CRISPR/Cas9-mediated knockout of the PRC2 core component, SUZ12. PRC2 loss led to not only significant increase, but also significant decrease of chromatin accessibility at 15,346 (16% of all ATAC peaks) and 20,099 genomic loci (21% of all ATAC peaks), respectively. PRC2 loss decreased the chromatin accessibility for IFNγ-responsive loci in M3 cells, resulting in dampened response to IFNγ stimulation.

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Genome-wide CRISPR/Cas9 screen to uncover effectors of PRC2 inhibition

Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that BMP-ACVR1 signaling pathway as a critical component for the anti-lymphoma efficacy of PRC2 inhibitor.

2024-04-04 | GSE232614 | GEO

EZH2 inhibition results in genome-wide PRC2 redistribution in cancer cell models

Project description:Upon EZH2 inhibitor treatment, PRC2 components EZH2 and SUZ12 are redistributed across the genome towards a small number of genomic loci that are refractory to H3K27me3 loss. Focal PRC2 accumulation and H3K27me3 retention occur primarily at CpG islands and transcription start sites of genes, with enrichment at canonical PRC2 nucleation sites. EZH2 and SUZ12 are present at low levels at actively transcribed TSSs, and this signal is lost with EZH2 inhibition.

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Inhibition of PRC2 activity by H3K36 methylation

Project description:Inhibition of PRC2 activity by H3K36 methylation

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Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Project description:A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

2018-08-31 | GSE118954 | GEO

Determine the chromatin association change of H3K27me3 and PRC2 in response to PRC2 subtype change or stable CTR9 KD in MCF7 cells

Project description:Determine the chromatin association change of H3K27me3 and PRC2 in response to PRC2 subtype change or stable CTR9 KD in MCF7 cells

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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

Analysis of whole genome expression change after NPD13668 treatment

Project description:EZH2 is a catalytic component of polycomb repressive complex 2 (PRC2), which contributes to aggressiveness in many types of cancers. Targeting EZH2/PRC2 has been challenged and now some inhibitors are under clinical trials for cancer treatments. Interestingly, anti-tumor effects of EZH2 is not always depend on H3K27 methyltransferase activity. In order to identify novel inhibitors against EZH2/PRC2, we established a chemical screening system based on measurement of reactivation of promoter activity, which is intrinsically silenced by EZH2/PRC2. We screened more than 300,000 small chemicals and identified 85 chemicals. After validation of reactivation of EZH2/PRC2 target genes, we identified chemical NPD13668 as a potential inhibitor of EZH2/PRC2 activity. To evaluate NPD13668 effect, we analysed whole genome expression change by using SurePrint G3 Human GE 8×60K array slides (G4851B, Agilent Technologies).

2019-02-01 | GSE122997 | GEO

EZH2 inhibition results in genome-wide PRC2 redistribution in cancer cell models

Project description:EZH2 inhibition results in genome-wide PRC2 redistribution in cancer cell models

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