Balanced E2F transcriptional output is essential for tumor suppression in the liver
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291068 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2129990.fastq.gz | Fastqsanger.gz | |||
| SRR2129991.fastq.gz | Fastqsanger.gz | |||
| SRR2129992.fastq.gz | Fastqsanger.gz | |||
| SRR2129988.fastq.gz | Fastqsanger.gz | |||
| SRR2129989.fastq.gz | Fastqsanger.gz |
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2016-07-01 | E-GEOD-71383 | biostudies-arrayexpress
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2016-07-01 | GSE71383 | GEO
Project description:We demonstrate that the cell cycle regulators, E2f /Dp and Rb, control the transcription of ribosomal proteins (RP) in Drosophila embryos. Mutation of E2f1 or Dp and over expression of Rbf1 increase and reduce RP transcription, respectively. Although E2f/Dp/Rb might exert this effect through a repressor complex, the regulatory regions of RP genes do not show an enrichment of canonical E2f binding sites. In addition, E2f1, Dp and Rbf1 also regulate the expression of RACK1, a ribosomal component and a negative regulator of cell cycle progression. These findings strengthen the coupling of cell cycle regulation to protein biosynthesis. Experiment Overall Design: Our study examines the genomic response of intact Drosophila embryos to the genetic manipulation of E2F/Rb pathway molecules. For over-expression experiments, Arm-Gal4 stocks were crossed to UAS-gene stocks for the following genes: E2f1/Dp, E2f2/Dp, Rbf1, and E2f1336-805 (a dominant negative form of E2f1 lacking the DNA binding domain) [16]. The E2f17172 and E2f191 null alleles were balanced by TM3[Kr-GFP]. Dpa2 and Dpa4 null alleles were balanced by CyO[Kr-GFP]. 14-16 hr E2f17172/E2f191 null mutant embryos were hand selected based on the absence of fluorescent Bolwigâs organs in Kr-GFP balanced stocks using a Zeiss stereomicroscope equipped with epifluorescence. E2f17172/E2f191 and Dpa2/Dpa4 null mutant embryos (8-10h) were selected using the COPASTM SELECT system for automated sorting of multi-cellular organisms. Eighteen RNA samples, two from each cross, were obtained from approximately 200 to 700 embryos per sample. For each cross, 2 h embryo collections were aged for 8 to 14 h at 25oC, quick frozen in an ethanol/dry ice mixture, and stored at -80 oC. The RNA was prepared for microarray analysis in accordance with Affymetrix instructions.
2008-06-15 | E-GEOD-7655 | biostudies-arrayexpress
Project description:Most E2F-binding sites repress transcription through the recruitment of Retinoblasoma (RB) family members until the end of the G1 cell-cycle phase. Although the MYB promoter contains an E2F-binding site, its transcription is activated shortly after the exit from quiescence, before RB family members inactivation, by unknown mechanisms. We had previously uncovered a nuclear factor distinct from E2F, Myb-sp, whose DNA-binding site overlapped the E2F element and had hypothesized that this factor might overcome the transcriptional repression of MYB by E2F-RB family members. We have purified Myb-sp and discovered that Myc-associated zinc finger proteins (MAZ) are major components. We show that various MAZ isoforms are present in Myb-sp and activate transcription via the MYB-E2F element. Moreover, while forced RB or p130 expression repressed the activity of a luciferase reporter driven by the MYB-E2F element, co-expression of MAZ proteins not only reverted repression, but also activated transcription. Finally, we show that MAZ binds the MYB promoter in vivo, that its binding site is critical for MYB transactivation, and that MAZ knockdown inhibits MYB expression during the exit from quiescence. Together, these data indicate that MAZ is essential to bypass MYB promoter repression by RB family members and to induce MYB expression.
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Project description:E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response
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Project description:Mutations in cancer are due in part to DNA cytosine deamination by APOBEC3B (A3B). While low in healthy tissues, A3B expression and activity are elevated in tumors and further increase in metastases. However, molecular mechanisms responsible for A3B transcriptional regulation are poorly understood. Here, we address whether the RB/E2F pathway, which is often dysregulated in breast cancer, is a molecular trigger of A3B overexpression. First, an A3B promoter-driven luciferase reporter was used to demonstrate reporter activation by disruption of only one out of five predicted E2F binding sites. Second, A3B-luciferase reporter activation was also triggered by expressing the BK polyomavirus T-antigen, which inactivates RB and thereby alleviates repression of E2F regulated genes. Importantly, A3B-luciferase reporter induction by BK polyomavirus T-antigen could not be further increased by mutating the functional E2F binding site. Third, both CRISPR disruption and targeted base substitutions in the endogenous E2F binding site caused strong A3B upregulation and confirmed importance of this regulatory element. Fourth, proteomics experiments showed that members of the DREAM and PRC1.6-complexes including multiple E2F family members are able to bind to wild-type but not E2F mutant promoter sequences. Finally, a combination of genetic and biochemical studies implicated E2F4 and E2F6 in endogenous A3B gene repression. Altogether, our studies demonstrate that A3B expression is suppressed in normal cells by the RB/E2F axis and that viral or mutational disruption of this pathway causes overexpression of this DNA deaminase in cancer and contributes mutational fuel to tumor evolution.
2020-10-19 | PXD020473 | Pride
Project description:The E2F family of transcription factors is an essential regulator of the cell cycle across all metazoan and is often deregulated in cancer. While their primary function is in cell cycle control, E2Fs also influence various cellular processes, such as apoptosis and metabolism. Previous studies in mice have shown that E2F deregulation particularly affect exocrine tissues such as the salivary gland and pancrease. However, the mechanisms behind exocrine cell sensitivity to E2F loss remain inadequately explored. Our lab recently discovered a novel alternatively spliced isoform of Drosophila de2f1, de2f1b, with an additional 16 amino acids than the canonical isoform of de2f1, de2f1a. de2f1b mutants have defects in development of polyploid tissues such as larval salivary glands (SG). Interestingly, SGs of de2f1b mutant shows DNA damage, accumulate cytoplasmic DNA and activation of immune response. This RNA-seq study is to create a gene expression profile of the de2f1b SGs to get a comprehensive understanding of the effects of de2f1b mutation in exocrine tissues.
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Project description:The E2F transcription factors constitute a core transcriptional network that governs cell division and oncogenesis in multi-cellular organisms, although their molecular mechanisms remain incompletely understood. Here, we show that elevated expression of the transcription factor FOXK1 promotes transcription of E2F target genes and cellular transformation. High expression of FOXK1 in patient tumors is also strongly correlated with E2F gene expression. Mechanistically, we demonstrate that FOXK1 is O-GlcNAcylated, and loss of this modification impairs FOXK1 ability to promote cell proliferation and tumor growth. We also show that expression of FOXK1 O-GlcNAcylation-defective mutants results in reduced recruitment of the H2AK119 deubiquitinase and tumor suppressor BAP1 to E2F target genes. This event is associated with a transcriptional repressive chromatin environment and reduced cell proliferation. Our results define an essential role of FOXK1 O-GlcNAcylation in co-opting the tumor suppressor BAP1 to promote cancer cell progression through orchestration of the E2F pathway.
2025-04-06 | GSE260904 | GEO
Project description:SK-MEL-2 cells treated with Ad-E2F-1 (MOI 2), Ad-E2F-1 (MOI 2)plus doxorubicin 0.1uM, or Ad-LacZ (MOI 2) plus doxorubicin 0.1uM Keywords: ordered
2005-06-03 | GSE2715 | GEO
Project description:Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and also associate with brain overgrowth. Nevertheless, activities of CHD8 in autism-relevant cell types are still poorly understood. Here we purify the CHD8 protein from human neural stem cells and determine its interaction partners by mass spectrometry. We identify the TRRAP-complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and TRRAP and CHD8 bind together to MYC- and E2F-target gene promoters in human neural stem cells. Acute depletion of CHD8 or TRRAP from human neural stem cells shows down-regulation of MYC- and E2F-target genes as most prominent gene-regulatory events. MYC and E2F factors are established oncogenes known to regulate cell growth. Our results link CHD8 to TRRAP in facilitating regulation of MYC- and E2F-target genes in neural stem cells.
2025-05-06 | PXD044582 | Pride