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Transcription profiling of mouse placentas from wild-type and Rb -/- knock-out mice and embronic day 11.5 placentas from wild-type and Rb -/-;E2f4 -/- double knock-outs reveals E2F4 cooperates with pRB in the development of extra-embryonic, not embryonic, tissues

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Charles Arthur Whittaker

PROVIDER: E-GEOD-13753 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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E2F4 cooperates with pRB in the development of extra-embryonic, not embryonic, tissues

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

TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

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

E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family

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.

2019-04-25 | GSE109684 | GEO

Transcription profiling of mouse epidermis from Rb(F19/F19)K14cre;Rbl2-/- (pRb-;p130-) mutants to analyse functional redundancies between retinoblastoma family members

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

Transcription profiling of human T98G cells during cell cycle in T98G

Project description:The mammalian Retinoblastoma (RB) family including pRB, p107, and p130 represses E2F target genes through mechanisms that are not fully understood. In D. melanogaster, RB-dependent repression is mediated in part by the multisubunit protein complex Drosophila RBF, E2F, and Myb (dREAM) that contains homologs of the C. elegans synthetic multivulva class B (synMuvB) gene products. Using an integrated approach combining proteomics, genomics, and bioinformatic analyses, we identified a p130 complex termed DP, RB-like, E2F, and MuvB (DREAM) that contains mammalian homologs of synMuvB proteins LIN-9, LIN-37, LIN-52, LIN-54, and LIN-53/RBBP4. DREAM bound to more than 800 human promoters in G0 and was required for repression of E2F target genes. In S phase, MuvB proteins dissociated from p130 and formed a distinct submodule that bound MYB. This work reveals an evolutionarily conserved multisubunit protein complex that contains p130 and E2F4, but not pRB, and mediates the repression of cell cycle-dependent genes in quiescence. Experiment Overall Design: Gene expression during the cell cycle in T98G cells. Cells were serum starved for 72 hours to induce G0 and then restimuated to enter cell cycle by serum addition. BrdU and FACS was done simultaneously to confirm their cell cycle phase.

2008-06-16 | E-GEOD-8537 | biostudies-arrayexpress

Gene expression profilie during cell cycle in T98G cells

Project description:The mammalian Retinoblastoma (RB) family including pRB, p107, and p130 represses E2F target genes through mechanisms that are not fully understood. In D. melanogaster, RB-dependent repression is mediated in part by the multisubunit protein complex Drosophila RBF, E2F, and Myb (dREAM) that contains homologs of the C. elegans synthetic multivulva class B (synMuvB) gene products. Using an integrated approach combining proteomics, genomics, and bioinformatic analyses, we identified a p130 complex termed DP, RB-like, E2F, and MuvB (DREAM) that contains mammalian homologs of synMuvB proteins LIN-9, LIN-37, LIN-52, LIN-54, and LIN-53/RBBP4. DREAM bound to more than 800 human promoters in G0 and was required for repression of E2F target genes. In S phase, MuvB proteins dissociated from p130 and formed a distinct submodule that bound MYB. This work reveals an evolutionarily conserved multisubunit protein complex that contains p130 and E2F4, but not pRB, and mediates the repression of cell cycle-dependent genes in quiescence. Keywords: Gene expression analysis during cell cycle

2007-07-21 | GSE8537 | GEO

Deregulation of the pRb-E2F4 axis alters epidermal homeostasis and favors tumor development

Project description:E2F/RB activity is altered in most human tumors. The retinoblastoma family of proteins plays a key role in regulating the progression of the cell cycle from the G1 to S phases. This is achieved through negative regulation of E2F transcription factors, important positive regulators of cell cycle entry. E2F family members are divided in two groups: activators (E2F1-E2F3a) and repressors (E2F3b-E2F8). E2F4 accounts for a large part of the E2F activity and is a main E2F repressor member in vivo. Perturbations in the balance from quiescence towards proliferation contribute to increased mitotic gene expression levels frequently observed in cancer. We have previously reported that combined Rb1-Rbl1 and Rb1-E2F1 ablation in epidermis produces important alterations in epidermal proliferation and differentiation, leading to tumor development. However, the possible roles of E2F4 in this context are still to be determined. Here we show the absence of any discernible phenotype in the skin of mice lacking of E2F4. In contrast, the inducible loss of Rb1 in the epidermis of E2F4-null mice produced multiple skin abnormalities including altered differentiation and proliferation, spontaneous wounds, carcinoma in situ development and stem cell perturbations. All these phenotypic alterations are associated with extensive gene expression changes, the induction of c-myc and the Akt activation. Moreover, the whole transcriptome analyses in comparison with previous models generated also revealed extensive changes in multiple repressive complexes and in transcription factor activity. These results point to E2F4 as a master regulator in multiple steps of epidermal homeostasis in Rb1 absence.

2016-07-09 | GSE84206 | GEO

Cell cycle exit and terminal differentiation independent of the Rb gene family during embryonic development

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.

2009-09-01 | GSE13408 | GEO

Transcription profiling of mouse Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo

2009-09-12 | E-GEOD-13408 | biostudies-arrayexpress

Transcription profiling of mouse osteoblast cell from wild-type and retinoblastoma tumor suppressor(Rb) knock-out.

Project description:Here we report the characterization of a novel role for the retinoblastoma protein (pRb) as a regulator of osteoblast adhesion. Abrogation of pRb in osteoblasts resulted in aberrant cadherin expression and loss of adherens junctions. This produced defects suggestive of a transformed phenotype such as impaired cell-to-cell adhesion, loss of contact-dependent growth arrest, and the capacity to evade anoikis. This also resulted in profound abnormalities in bone structure. Consistent with this, microarray analyses showed that pRb regulates a wide repertoire of osteoblast cell adhesion genes. In addition, pRb loss also resulted in altered expression and function of several known regulators of cellular adhesion and adherens junction assembly, such as the Rho GTPase Rac1 and the merlin tumor suppressor. Taken together, our results show that pRb controls cell adhesion by regulating the expression and adherens junction components and by regulating the function of molecules involved in adherens junction assembly and stability. Microarray results helped us to portrait the overall influence on cell adhesion via both individual genes and pathway analysis. Experiment Overall Design: MC3T3 cells were obtained from immortalizing primary cultured mouse osteoblast cells by using 3T3 protocol. There are 3 biological replicates for each group, 6 samples in total were analyzed.

2009-12-14 | E-GEOD-19299 | biostudies-arrayexpress

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