GEO accession GSE278461 is currently private and is scheduled to be released on Sep 01, 2025.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1167313 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30843000_1.fastq.gz | Fastqsanger.gz | |||
| SRR30843000_2.fastq.gz | Fastqsanger.gz | |||
| SRR30843001_1.fastq.gz | Fastqsanger.gz | |||
| SRR30843001_2.fastq.gz | Fastqsanger.gz | |||
| SRR30843002_1.fastq.gz | Fastqsanger.gz |
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Project description:E2F is a family of master transcription regulators involved in mediating diverse cell fates, and loss of control of the pathway is regarded as a hallmark of cancer. Recent studies have highlighted the pRb-E2F axis as a regulator of a large cellular network, which in addition to its classical target genes includes RNA splicing and non-coding genes. Here, we have addressed the generality of these effects by studying the role of the other key components of the pathway, including pRb, DP and PRMT5. Like E2F1, both pRb and DP1 influence transcription and alternative RNA splicing (AS) which is additionally impacted by PRMT5 activity. A detailed proteomics analysis of the E2F1 interactome revealed SRSF2 and HNRNPC as partner proteins that assist E2F1 in mediating the effects on RNA splicing. The ability of E2F1 to influence AS activity was apparent as cells progress through the cell cycle and during the DNA damage response. Our results highlight the role of the pRb-E2F pathway in mediating cell cycle regulation of gene expression mediated by transcription and RNA splicing, and provide a mechanistic understanding for how this is likely to occur.
2026-02-04 | GSE278461 | GEO
Project description:E2F is a family of master transcription regulators involved in mediating diverse cell fates, and loss of control of the pathway is regarded as a hallmark of cancer. Recent studies have highlighted the pRb-E2F axis as a regulator of a large cellular network, which in addition to its classical target genes includes RNA splicing and non-coding genes. Here, we have addressed the generality of these effects by studying the role of the other key components of the pathway, including pRb, DP and PRMT5. Like E2F1, both pRb and DP1 influence transcription and alternative RNA splicing (AS) which is additionally impacted by PRMT5 activity. A detailed proteomics analysis of the E2F1 interactome revealed SRSF2 and HNRNPC as partner proteins that assist E2F1 in mediating the effects on RNA splicing. The ability of E2F1 to influence AS activity was apparent as cells progress through the cell cycle and during the DNA damage response. Our results highlight the role of the pRb-E2F pathway in mediating cell cycle regulation of gene expression mediated by transcription and RNA splicing, and provide a mechanistic understanding for how this is likely to occur.
2026-02-09 | PXD056505 | Pride
Project description:The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
2021-10-29 | GSE182884 | GEO
Project description:The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
2021-10-29 | GSE149519 | GEO
Project description:The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
2021-10-29 | GSE149537 | GEO
Project description:The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1∆G) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1∆G/∆G MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1∆G/∆G MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1∆G/∆G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1∆G/∆G MEFs is responsive to p16 expression, indicating that the ΔG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1∆G/∆G mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified.
2014-04-14 | GSE54924 | GEO
Project description:The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1DeltaG) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1DeltaG/DeltaG MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1DeltaG/DeltaG MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1DeltaG/DeltaG cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1DeltaG/DeltaG MEFs is responsive to p16 expression, indicating that the DeltaG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1DeltaG/DeltaG mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified. Total RNA was extracted from littermate paired WT, DeltaG and null MEFs induced to enter quiencense by Serum deprivation. Expresssion levels were analyzed by Affymetrix GeneChip Mouse Gene 1.0ST Array. Relative expression was determined by BRB-Array Tools software to generate RMA values.
2014-04-14 | E-GEOD-54924 | biostudies-arrayexpress
Project description:The epidermal-specific ablation of Rb gene leads to increased proliferation, aberrant differentiation, and the disengagement of these processes in vivo and in vitro. These differences in phenotype are more severe with the loss of p107, demonstrating the functional compensation between pRb and p107. As p107 and p130 also exert overlapping functions in epidermis, we have generated Rb(F19/F19)K14cre;Rbl2-/- (pRb-;p130-) mice to analyze possible functional redundancies between pRb and p130. The epidermal phenotype was very similar between pRb- and pRb-;p130- mice, suggesting that pRb and p130 activities are not redundant in epidermis. Importantly, we can correlate the proliferation differences with specific changes in gene expression between pRb-, pRb-;p107- and pRb-;p130- primary keratinocytes using microarray analysis, and explain the phenotypes in the context of altered E2F expression and functionality. Our findings support a model in which the distinct retinoblastoma family members, in conjunction with E2F members, play a central role in regulating epidermal homeostasis through specific or overlapping activities. Experiment Overall Design: Total RNA from pooled cells from each genotype were analyzed, per duplicate (pRb-/-;p107-/-, or pRb-/-;p130-/-) or triplicate (wild type, or pRb-/-), in mouse microarrays. Comparison was performed between the 4 different genotypes.
2008-06-16 | E-GEOD-9562 | biostudies-arrayexpress
Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient
2023-07-01 | GSE180530 | GEO
Project description:Homozygous mutation of the murine retinoblastoma tumor suppressor gene, Rb, results in embryonic lethality between E13.5 and E15.5 with defects in cellular proliferation, differentiation and apoptosis. Many of these defects are suppressed by mutation of an activating E2F, E2f1 or E2f3, indicating that they are key downstream targets of the retinoblastoma protein, pRB. In this study, we assess how E2F4 contributes to the developmental consequences of pRb-loss. In stark contrast to the activating E2Fs, the homozygous mutation of E2f4 shortened the lifespan of Rb-/- embryos. This resulted from an exacerbation of the placental defect of the Rb-/- mice indicating that E2F4 and pRB cooperate in the development of this tissue. Further analyses indicated that this defect reflects an increase in trophectoderm-like cells. Under conditions where the placenta was wild-type but the embryo mutant for E2f4 and pRb embryos survived to birth and exhibited all of the defects that were observed in the E2f4 and Rb single mutant embryos. Thus, while pRB and E2F4 cooperate in placental development, they play largely non-overlapping roles the development of many embryonic tissues. Keywords: genetically modified tissue comparison
2009-06-08 | GSE13753 | GEO