E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family
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ABSTRACT:
PROVIDER: PRJNA431650 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6513310_1.fastq.gz | Fastqsanger.gz | |||
| SRR6513310_2.fastq.gz | Fastqsanger.gz | |||
| SRR6513301_1.fastq.gz | Fastqsanger.gz | |||
| SRR6513301_2.fastq.gz | Fastqsanger.gz | |||
| SRR6513311_1.fastq.gz | Fastqsanger.gz |
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Project description:E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. This role for E2F4 is independent of the RB family. Accordingly, E2F4 functionally interacts with chromatin regulators associated with gene activation and we observed decreased histone acetylation at the promoters of cell cycle genes and E2F targets upon loss of E2F4 in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that provide insights into the biology of rapidly dividing cells.
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Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.
2019-04-26 | PXD008796 | Pride
Project description:E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. This role for E2F4 is independent of the RB family. Furthermore, E2F4 functionally interacts with chromatin regulators associated with gene activation and we observed decreased histone acetylation at the promoters of cell cycle genes and E2F targets upon loss of E2F4 in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that provide insights into the biology of rapidly dividing cells.
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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. Experiment Overall Design: In one experiment, embryonic Day 13.5 placentas from wild-type and Rb -/- knock-out mice were compared. In the second experiment, embronic day 11.5 placentas from wild-type and Rb -/-;E2f4 -/- double knock-out mice were compared.
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Project description:The retinoblastoma cell cycle regulator pRb and the two related proteins p107 and p130 are thought to suppress cancer development both by inhibiting the G1/S transition of the cell cycle in response to growth-arrest signals and by promoting cellular differentiation. Here, we investigated the phenotype of Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo and in culture. Confirming the central role of the Rb gene family in cell cycle progression, TKO mouse embryos did not survive past mid-gestation and differentiating TKO cells displayed increased proliferation and cell death. However, patterning and cell fate determination were largely unaffected in these TKO embryos. Furthermore, a number of TKO cells, including in the neural lineage, were able to exit the cell cycle in G1 and terminally differentiate. This ability of Rb family TKO cells to undergo cell cycle arrest was associated with the repression of target genes for the E2F6 transcription factor, uncovering a pRb-independent control of the G1/S transition of the cell cycle. These results show that the Rb gene family is required for proper embryonic development but is not absolutely essential to induce G1 arrest and differentiation in certain lineages.
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Project description:Loss of Rb family in HSC results in their sustained proliferation, impaired homeostasis and extramedullar mobility.
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Project description:Cell cycle deregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb- and Rb family (Rb, p107, and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and form tumors when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from Rb -/-; p107 -/-; p130 -/- (Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated DNA double-strand break (DSB) repair pathway without increasing the tri-methylation of histone H4 at lysine 20 (H4K20M3), which is known to protect from DNA damage. The activation of DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly-born cortical neurons from progenitors epigenetically become protected from DNA damage and cell division in a Rb family-dependent manner.
2014-01-01 | GSE37577 | GEO
Project description:Cell cycle deregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb- and Rb family (Rb, p107, and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and form tumors when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from Rb -/-; p107 -/-; p130 -/- (Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated DNA double-strand break (DSB) repair pathway without increasing the tri-methylation of histone H4 at lysine 20 (H4K20M3), which is known to protect from DNA damage. The activation of DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly-born cortical neurons from progenitors epigenetically become protected from DNA damage and cell division in a Rb family-dependent manner. 3 samples of pCAG-control, pCAG-RbTKO, pMAP2-control, and pMAP2-RbTKO cells
2014-01-01 | E-GEOD-37577 | biostudies-arrayexpress