NANOG prion-like assembly mediates DNA bridging
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ABSTRACT:
PROVIDER: PRJNA787568 | ENA |
REPOSITORIES: ENA
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Project description:NANOG is a key stem cell pluripotency factor. NANOG’s unique ability to form prion-like assemblies provides a cooperative and concerted DNA bridging mechanism essential for chromatin reorganization and dose-sensitive activation of ground state pluripotency. We take advantage of Hi-C and ChIP-seq experiments to directly address whether NANOG can bridge DNA elements together in human cells, and our results support this.
2022-02-15 | GSE190567 | GEO
Project description:Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly-treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
2020-01-31 | GSE144028 | GEO
Project description:Prions consist of aggregates of abnormal conformers of cellular prion protein (PrPC). They propagate by recruiting host-encoded PrPC although the critical interacting proteins and the reasons for the differences in susceptibility of distinct cell lines and populations are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by PrPC expression differences, to identify such factors. We examined the transcriptomes of prion-resistant revertants, isolated from highly susceptible cells, and identified a gene expression signature associated with susceptibility. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP deposits. Loss-of-function of nine of these genes significantly increased susceptibility. Remarkably, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation rates. This indicates that prion replication may be controlled by MMPs at the ECM in an integrin-dependent manner.
2014-07-31 | GSE56275 | GEO
Project description:This report describes our study of the efficacy and the potential mechanism underlying the anti-prion action of a new anti-prion compound having a glycoside structure in prion-infected cells. The study revealed involvements of two factors in the mechanism of the compound action: interferon and a microtubule nucleation activator, phosphodiesterase 4D interacting protein. In particular, phosphodiesterase 4D interacting protein was suggested to be important in regulating the trafficking or fusion of prion protein-containing vesicles or structures in cells. The findings of the study are expected to be useful not only for the elucidation of cellular regulatory mechanisms of prion protein, but also for the implication of new targets for therapeutic development. Prion-infected N167 cells were treated with either anti-prion glycoside compound (Gly-9) or control glycoside compound (Gly-14) at a dose of 5 M-NM-<g/mL for three days. Then, gene expression profiles were analyzed by DNA microarray analysis. Experiments were performed in quadruplicate.
2014-02-22 | E-GEOD-55241 | biostudies-arrayexpress
Project description:This report describes our study of the efficacy and the potential mechanism underlying the anti-prion action of a new anti-prion compound having a glycoside structure in prion-infected cells. The study revealed involvements of two factors in the mechanism of the compound action: interferon and a microtubule nucleation activator, phosphodiesterase 4D interacting protein. In particular, phosphodiesterase 4D interacting protein was suggested to be important in regulating the trafficking or fusion of prion protein-containing vesicles or structures in cells. The findings of the study are expected to be useful not only for the elucidation of cellular regulatory mechanisms of prion protein, but also for the implication of new targets for therapeutic development.
2014-02-22 | GSE55241 | GEO
Project description:A comparison of prion infected and non-infected samples from neuroblastoma cells (N2a), and a comparison of prion infected and non-infected samples from hypothalmus cells (GT1). 11 dual-color DNA-chip hybridizations of cDNAs were made. Keywords: other
2005-08-24 | GSE1803 | GEO
Project description:A comparison of prion infected and non-infected samples from neuroblastoma cells (N2a), and a comparison of prion infected and non-infected samples from hypothalmus cells (GT1). 11 dual-color DNA-chip hybridizations of cDNAs were made. Keywords: other
2010-06-09 | E-GEOD-1803 | biostudies-arrayexpress
Project description:While prion infections have been extensively characterized in the laboratory mouse, little is known regarding the molecular responses to prions in other rodents. To explore these responses and make comparisons, we generated a prion disease in the laboratory rat by successive passage of mouse RML prions. Here we describe the accumulation of prions and associated pathology in the rat and describe the transcriptional impact throughout prion disease. Comparative transcriptional profiling between laboratory mice and rats suggests that similar molecular processes are unfolding in response to prion infection. At the level of individual transcripts, however, variability exists between mice and rats and many genes deregulated in mouse scrapie are not affected in rats. Notwithstanding these differences, many transcriptome responses are conserved between mice and rats infected with scrapie. Our findings highlight the usefulness of comparative approaches to understanding neurodegeneration and prion diseases in particular.
2015-09-01 | GSE63930 | GEO
Project description:While prion infections have been extensively characterized in the laboratory mouse, little is known regarding the molecular responses to prions in other rodents. To explore these responses and make comparisons, we generated a prion disease in the laboratory rat by successive passage of mouse RML prions. Here we describe the accumulation of prions and associated pathology in the rat and describe the transcriptional impact throughout prion disease. Comparative transcriptional profiling between laboratory mice and rats suggests that similar molecular processes are unfolding in response to prion infection. At the level of individual transcripts, however, variability exists between mice and rats and many genes deregulated in mouse scrapie are not affected in rats. Notwithstanding these differences, many transcriptome responses are conserved between mice and rats infected with scrapie. Our findings highlight the usefulness of comparative approaches to understanding neurodegeneration and prion diseases in particular. We Adapted RML Mouse Scrapie into Rats and measured the resulting gene expression changes in brain as a result of disease progression. Rats were infected by intracranial inoculation with prion isolates obtained by adaptation of mouse RML scrapie prions into rats. Brain samples were collected from third and fourth passage infected rats and age-matched controls at specified timepoints and gene expression profiles obtained. For each time point, 3 diseased and control brain samples were profiled.
2015-09-01 | E-GEOD-63930 | biostudies-arrayexpress
Project description:Sheep scrapie (Sc) is the classical transmissible spongiform encephalopathy (prion disease). The conversion of normal cellular prion protein (PrPC) to disease-associated prion protein (PrPSc) is a fundamental component of prion disease pathogenesis. The molecular mechanisms contributing to prion diseases and the impact of PrPSc accumulation on cellular biology are not fully understood. To define the molecular changes associated with PrPSc accumulation, primary sheep microglia were inoculated with PrPSc and then the transcriptional profile of these PrPSc-accumulating microglial cells was compared to the profile of PrPSc-lacking microglial cells using the Affymetrix Bovine Genome Array. The experimental design included three biological replicates, each with three technical replicates, and samples that were collected at the point of maximal PrPSc accumulation levels as measured by ELISA. The array analysis revealed 19 upregulated genes and 30 downregulated genes in PrPSc-accumulating microglia. Three transcripts (CCL2, SGK1, and AASDHPPT) were differentially regulated in a direction similar to previous reports from mouse or human models, whereas the response of three other transcripts (MT1E, NR4A1, PKP2) conflicted with previous reports. Overall, the results demonstrated a limited transcriptional response to PrPSc accumulation, when compared to microglia and macrophage cultures infected with other agents such as viruses and bacteria. This is the first microarray-based analysis of prion accumulation in primary cells derived from a natural TSE-host. Keywords: disease state analysis
2008-09-06 | GSE12688 | GEO