Snip1 and PRC2 coordinate the intrinsic apoptosis, cell division, and neurogenesis in the developing brain [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212103 | GEO | 2023/07/12
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-12 | GSE212445 | GEO
Project description:Approximately 3 × 105 NPCs sorted for Sox2-eGFP were mixed with 3 × 104 Drosophila S2 cells per reaction. We performed CUT&RUN using the protocol developed by the Henikoff lab (Skene and Henikoff, 2017). In brief, Bio-Mag®Plus Concanavalin-A (Con A) coated beads (Bangs Laboratories BP531) were washed and activated with Binding buffer. Nuclei of NPCs with S2 spike-in were gently prepared (see Subcellular Protein Extraction section). Activated Con A beads and nuclei were then mixed and rotated for 5 min at room temperature. They were then blocked with Digitonin block buffer for 5 min at room temperature. 0.5-1 μg of primary antibody with 0.25 μg Spike-in antibody (Active Motif 61686) diluted in Digitonin block buffer was added to the bead-nuclei mixture and incubated for 3 hours (histone marks) or O/N (the rest) at 4 °C. Beads were washed three times with Digitonin block buffer and incubated with pA-MNase for 1 hour at 4 °C. Beads were washed three times with Wash buffer and incubated in Wash buffer for 10 min on ice. The pA-MNase was activated by incubating the beads with 2 mM CaCl2 for 25 min on ice and quenched by adding the Stop buffer. DNA was released from the beads by incubating them for 30 min at 37 °C and collected by centrifugation at 16,000 x g for 5 min at 4 °C. DNA was then isolated by using a phenol/chloroform extraction method.
2023-07-12 | GSE212444 | GEO
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.
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Project description:To identify the potential functions of SRSF10 in neural progenitor cells and neocortex development, we constructed SRSF10 flox/flox mice, and conditionally knock out the SRSF10 in the neural progenitor cells by breeding with Nestin-Cre mice.
2023-05-30 | GSE225647 | GEO
Project description:Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wildtype tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.
2022-06-18 | GSE206003 | GEO
Project description:Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wildtype tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.
2022-06-18 | GSE206000 | GEO
Project description:Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27me3, which characterizes many silenced genes including those on the inactive X-chromosome. Here we interrogate the role of core PRC2 protein EED in X-linked gene silencing by assessing allele-specific X-linked gene expression in WT and Eed-/- hybrid mouse trophoblast stem cells (TSCs) harboring a 129/S1-derived maternal X-chromosome and a JF1/Ms-derived paternal X-chromosome. This study generates mRNA-seq data for WT and Eed-/- TSCs, which undergo imprinted inactivation of the paternal X-chromosome. RNA-seq data was mapped allele-specifically to in silico strain-specific maternal and paternal reference genomes, generated based on known single nucleotide polymorphisms. We find that EED loss abrogates H3K27me3 and expression of Xist lncRNA, which is required for X-inactivation, however, despite the absence of H3K27me3 and Xist, only a subset of PRC2 target genes are derepressed in Eed-/- TSCs.
2017-04-07 | GSE84681 | GEO
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.
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Project description:To assess the effects of UNC6852 treatment on cellular protein levels more broadly, we performed global proteomics experiments using tandem mass tag (TMT) quantification comparing HeLa cells treated with UN6852 (10 μM, 24 hrs) to DMSO treated control cells. Whole proteome analysis resulted in the identification of >60,000 peptides corresponding to 5,452 quantifiable proteins. Notably, these data revealed that EED and EZH2 were selectively degraded by UNC6852 within the proteome.
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Project description:Analysis of changes in gene expression in skin epidermis upon conditional knockout of the essential Polycomb repressive complex 2 (PRC2) subunit Eed. Loss of Eed in skin epithelium leads to de-repression of key Merkel-differentiation genes, which are known PRC2 targets, and results in ectopic formation of Merkel cells that are associated with all hair types. Gene expression analysis: To determine the changes in gene expression in skin epidermis upon conditional knockout of Eed, total RNA was isolated from skin epidermis in four biologic replicates from cells in different conditions and hybridized to SurePrint G3 Mouse GE 8X60K microarrays (Agilent).
2016-06-14 | E-GEOD-83244 | biostudies-arrayexpress