PRC2 molecule EZH1 is a target of epigenetic therapy of neuroblastoma
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ABSTRACT:
PROVIDER: PRJNA779921 | ENA |
REPOSITORIES: ENA
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Project description:In the present study, we found that EZH1 depletion in MYCN-amplified neuroblastoma cells resulted in significant cell death as well as xenograft inhibition. EZH1 depletion decreased the level of H3K27me1; the interaction and protein stabilization of MYCN and EZH1 appear to play roles in epigenetic transcriptional regulation. Transcriptome analysis of EZH1-depleted cells resulted in down-regulation of the cell cycle progression-related pathway. In particular, GSEA revealed down-regulation of reactome E2F-mediated regulation of DNA replication along with key genes of this process, TYMS, POLA2, and CCNA1. TYMS and POLA2 were transcriptionally activated by MYCN and EZH1-related epigenetic modification. Treatment with the EZH1/2 inhibitor UNC1999 also induced cell death, decreased H3K27 methylation, and reduced the levels of TYMS in NB cells. Previous reports indicated neuroblastoma cells are resistant to 5-fluorouracil (5-FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN-amplified neuroblastoma cells to 5-FU treatment, suggesting that EZH inhibition may be an effective strategy for development of a new epigenetic treatment for neuroblastoma.
2022-11-08 | GSE188673 | GEO
Project description:PRC2 molecule EED is a target of epigenetic therapy of neuroblastoma
| PRJNA760445 | ENA
Project description:Epigenetic modification by polycomb repressive complex (PRC) molecules appears to have a role in tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic Ectoderm Development (EED) is a member of PRC2 complex and binds the H3K27me3 mark deposited by EZH2, via propagation on adjacent nucleosomes. Here we studied the molecular roles of EED in MYCN-amplified neuroblastoma cells by using EED-knocked down shRNAs, EED-knocked out sgRNAs, and EED small molecule inhibitor EED226. EED suppression profoundly inhibited the NB cell proliferation and flat-and soft agar colony formation. Transcriptome analysis by microarray of the EED-KD NB cells indicated the de-repression of the cell cycle regulated and differentiation-related genes; GSEA analysis results suggested that cell cycle repressed gene sets were strongly upregulated. Further, epigenetic treatment by the combination of EED inhibitor EED226 and HDAC inhibitor valproic acid effectively suppressed NB cell proliferation and colony formation. The combinatory epigenetic treatment up-regulated the cell cycle regulation- and differentiation-related genes.
2022-09-03 | GSE183369 | GEO
Project description:We previously reported the requirement of Polycomb Repressive Complex 2 (PRC2) for spermatogenesis through transcriptional repression of somatic genes and meiosis-specific genes. To characterize how PRC2's two methyltransferase subunits, EZH1 and EZH2, regulate histone H3 lysine 27 (H3K27) methylation during germ cell development, we generated mouse models with a germline ablation of EZH1 and/or EHZ2. Only the combined loss of EZH1 and EZH2 caused a depletion of global H3K27me3 marks and meiotic arrest in spermatocytes. Genome-wide analysis of H3K27me3 in spermatogenic cells revealed that a noncanonical EZH1-PRC2 could establish and maintain this histone mark on somatic genes and certain meiotic genes. Consistent with it having active enhancers in testis, Ezh1 was not only abundant in highly differentiated spermatocytes but also in actively proliferating progenitor and stem germ cells. Taken together, our findings suggest that the expression level of Ezh1 determines the restoration of H3K27 methylation in the absence of the canonical EZH2-PRC2.
2017-03-07 | GSE95225 | GEO
Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1 Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1 Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2 chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1 Q571R but not with the corresponding EZH2 Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1 Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1 Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.
2026-07-03 | GSE294320 | GEO
Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1 Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1 Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2 chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1 Q571R but not with the corresponding EZH2 Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1 Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1 Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.
2026-07-03 | GSE294325 | GEO
Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1 Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1 Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2 chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1 Q571R but not with the corresponding EZH2 Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1 Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1 Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.
2026-07-03 | GSE294323 | GEO
Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1 Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1 Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2 chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1 Q571R but not with the corresponding EZH2 Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1 Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1 Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.
2026-07-03 | GSE294321 | GEO
Project description:Circadian rhythmicity of gene expression is a conserved feature of cell physiology. This involves fine tuning between transcriptional and post-transcriptional molecular mechanisms, strongly dependent on the metabolic state of the cell, which guarantees adaptive plasticity of tissue-specific genetic programs. Dynamics of epigenome structure and epigenetic regulators support this plasticity. However, the intermingle between epigenome and RNA Pol II rhythmicity remains to be investigated. Here we identify the Polycomb group (PcG) protein EZH1 as a gateway bridging function regulating periodic alternation between chromatin mediated silencing and active transcription in post-mitotic skeletal muscle cells. We show that PRC2-EZH1 core components are under direct regulation of BMAL1, and show an oscillatory behavior and a regulated periodic assembly of PRC2-EZH1 complex. Instead at alternate Zeitgeber points, EZH1 becomes essential for circadian gene expression, through stabilization of RNA Pol II preinitiation complex controlling nascent transcription process. Collectively, our data show that EZH1 depending on the stoichiometry of its partners guarantees both negative and positive modulation of RNA Pol II activity, resulting in oscillatory transcription.
2024-10-11 | PXD035453 | Pride
Project description:Circadian rhythmicity of gene expression is a conserved feature of cell physiology. This involves the fine tuning between transcriptional and post-transcriptional molecular mechanisms, strongly dependent on the metabolic state of the cell that guarantees intrinsic plasticity of tissue specific genetic programs. To support the plastic properties a key role is played by the dynamics of epigenome structure and its regulators. Here we investigate the role of the Polycomb cell memory complex PRC2-EZH1 in regulating transcriptional rhythmicity in post-mitotic skeletal muscle cells. We show that PRC2-EZH1 core components are under direct regulation of BMAL1, show an oscillatory behavior and control both silencing and activation of target genes. Fully assembled PRC2-EZH1 complex negatively regulates cyclic expression of direct targets through modulation of cyclic H3K27me3 status. Conversely, we show that EZH1 regulates constitutive circadian genes expression, through stabilization of RNA Pol II machinery and maintenance of transcription process fidelity. Collectively, these findings unveil the dual and multi role of PcG in circadian gene regulation in adult skeletal muscle cells, and the plastic nature of PcG cell memory system in somatic cells.
2025-01-03 | GSE198409 | GEO