PRC2 molecule EZH1 is a target of epigenetic therapy of neuroblastoma
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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: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:Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification. Analysis of genomic occupancy of EZH1, EZH2, EED, SUZ12, various histone marks and transcription factors in primary human fetal liver proerythroblasts by ChIP-seq. Sample GSM970262 was used as the input DNA sample.
2015-01-01 | E-GEOD-59087 | biostudies-arrayexpress
Project description:PRC2 proteins EZH1 and EZH2 regulate postnatal hepatic maturation
| PRJNA488479 | ENA
Project description:Ezh1 is a protein member of PRC2. Ezh1 has been described as a functional repressor gene, such as its homologous Ezh2. We are investigating the role of Ezh1 in hematopoietic stem cells, aging, self-renewal and differentiation. We used microarrays to detail the global program of gene expression in LSK cells from mice with knocked-down expression of Ezh1. LSK cells from EZH1 knockout and control mice were marked and isolated by fluorescence-activated cell sorting. 2 replicates each.
2012-03-06 | E-GEOD-36288 | biostudies-arrayexpress
Project description:Polycomb Repressive Complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during hematopoiesis. We examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 sub-complex lacking EED. We provide evidence that EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin domains in the absence of H3K27me3, and positively regulate gene expression. Loss of EZH2 expression leads to global repositioning of EZH1 chromatin occupancy to EZH2 targets. Moreover, we demonstrate that an erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers during erythropoiesis. Thus, the lineage- and developmental stage-specific regulation of PRC2 expression and subunit composition leads to a switch from canonical silencing to non-canonical PRC2 functions during blood stem cell specification. Transcriptional profiling in primary human fetal liver proerythroblasts upon lentiviral shRNA-mediated knockdown of EZH1, EZH2, EED, or SUZ12 by RNA-seq analysis.
2015-01-01 | E-GEOD-59089 | biostudies-arrayexpress
Project description:Trimethylation on H3K27 (H3K27me3) mediated by Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem cell (ESC) identity and pluripotency. EZH2, the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase that methylates H3K27 and mediates transcriptional silencing. Analysis of Ezh2(-/-) ESCs suggests existence of an additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a noncanonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin and preferentially preserves this mark on development-related genes in Ezh2(-/-) ESCs. Depletion of Ezh1 in cells lacking Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ESC identity. Ezh1 partially complements Ezh2 in executing pluripotency during ESC differentiation, suggesting that cell-fate transitions require epigenetic specificity.
2009-03-25 | GSE15388 | GEO