E2F regulation of Phosphoglycerate kinase (Pgk) gene is functionally important in Drosophila development
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ABSTRACT:
PROVIDER: PRJNA897930 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22179395_1.fastq.gz | Fastqsanger.gz | |||
| SRR22179395_2.fastq.gz | Fastqsanger.gz | |||
| SRR22179396_1.fastq.gz | Fastqsanger.gz | |||
| SRR22179396_2.fastq.gz | Fastqsanger.gz | |||
| SRR22179397_1.fastq.gz | Fastqsanger.gz |
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Project description:Our study focuses on understanding the changes in chromatin accessibility in the Pgk-DeltaE2F mutant that takes place during flight muscles development in Drosophila. E2F binding sites were mutated upstream Pgk gene. E2F/Dp/Rbf were no longer recruited to this regulatory region. As a result of this, the expression of Pgk mRNA was downregulated, which led to reduced levels in many metabolites that are glycolytic and TCA intermediates. Using ATAC-seq we determined that there was a global reduction in chromatin accessibility in the mutant compared to control, and it was accompagnied by a widespread reduction in gene expression, including metabolic genes. In addition we identified a broad range of phenotypes when analyzing the functional relevance of E2F regulation on Pgk gene. These phenotypes range from low ATP content, abnormal mitochondrial morphology, shortened life span to embrionic lethality. Furthermore, defects in high-energy consuming organs, such as ovaries and muscles, were found. In sum, our results illustrate the pleiotropic effects on metabolism, gene expression and development in the Pgk-deltaE2F animals, which underlies the importance of E2F regulation on a single E2F target, Pgk.
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Project description:The canonical role of the transcription factor E2F is to control the expression of cell cycle genes by binding to the E2F sites in their promoters. However, the list of putative E2F target genes is extensive and includes many metabolic genes, yet the significance of E2F in controlling the expression of these genes remains largely unknown. Here, we used the CRISPR/Cas9 technology to introduce point mutations in the E2F sites upstream of five endogenous metabolic genes in Drosophila melanogaster. We found that the impact of these mutations on both the recruitment of E2F and the expression of the target genes varied, with the glycolytic gene, Phosphoglycerate kinase (Pgk), being mostly affected. The loss of E2F regulation on the Pgk gene led to a decrease in glycolytic flux, tricarboxylic acid cycle intermediates levels, adenosine triphosphate (ATP) content, and an abnormal mitochondrial morphology. Remarkably, chromatin accessibility was significantly reduced at multiple genomic regions in PgkΔE2F mutants. These regions contained hundreds of genes, including metabolic genes that were downregulated in PgkΔE2F mutants. Moreover, PgkΔE2F animals had shortened life span and exhibited defects in high-energy consuming organs, such as ovaries and muscles. Collectively, our results illustrate how the pleiotropic effects on metabolism, gene expression, and development in the PgkΔE2F animals underscore the importance of E2F regulation on a single E2F target, Pgk.
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Project description:We identified a role for E2F-2 in the regulation of erythroblast nuclear condensation and enucleation. To help define the mechanism by which E2F-2 regulates these processes, we performed RNA-sequencing on undifferentiated hematopoietic cells and sorted, orthochromatic erythroblasts obtained from wildtype and E2F-2 knockout animals. In undifferentiated progenitor cells we find a limited number of differentially expressed genes associated with E2F-2-loss, likely due to compensation by other E2F family members. However, in late-stage erythroblasts, loss of E2F-2 results in the down-regulation of over 1200 genes. Our subsequent analyses focused on the role of a particular mitotic kinase, Citron Rho-interacting kinase, which we find is induced in an E2F-2-dependent manner during terminal erythroid maturation and identify as a novel regulator of erythroblast enucleation.
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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. Keywords: genotype response
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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: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.
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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.
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Project description:Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlie numerous pathologies including cancer. FOXK1 and FOXK2 (FOXK1/2) transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation. While FOXK1/2 possesses many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and often contradictory. FOXK1, but less FOXK2, is known to have oncogenic properties as higher expression levels of FOXK1 has been observed in several cancers and is correlated with tumor progression, invasion, and metastasis. However, the molecular mechanism by which FOXK1 exert its oncogenic properties in caner remains unknown. Here we show that elevated expression of FOXK1, but not FOXK2, in normal human fibroblasts promotes transcription of E2F target genes associated with increased proliferation and delayed senescence entry. Fibroblasts overexpressing FOXK1 are also more prone to cellular transformation with minimal oncogenic combinations, suggesting important oncogenic proprieties of FOXK1. Mechanistically, we found that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle and its highest levels coincides with the G1/S phase transition. Moreover, FOXK1 O-GlcNAcylation is increased following cell transformation and loss of this modification leads to decreased FOXK1 ability to promote cellular transformation and tumor growth. Cells overexpressing FOXK1 O-GlcNAcylation-defective mutants have lower E2F1 expression, cell proliferation, and tumour growth. Our results define a distinct role of FOXK1 via O-GlcNAcylation in controlling the cell cycle through the orchestration of the E2F pathway.
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