TFAP2C and HNRNPK control cellular bioenergetic metabolism and prion propagation [CRISPR screen]
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ABSTRACT:
PROVIDER: PRJNA1174705 | ENA |
REPOSITORIES: ENA
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Project description:Heterogenous Nuclear Ribonucleoprotein K (HNRNPK) is a limiting factor for prion propagation. However, little is known about the function of hnRNP_K other that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify functional epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2γ (TFAP2C) mitigated the survival of hnRNP_K-depleted LN-229 and U-251MG cells, whereas its overexpression hypersensitized cells to the loss of hnRNP_K. HNRNPK ablation induced downregulation of genes related to lipid and glucose metabolism, decreased cellular ATP and enhanced catabolism through modulation of the mTOR and AMPK pathways. Conversely, TFAP2C overexpression promoted mTOR anabolic activity, and its deletion countered the energetic crisis resulting from HNRNPK ablation. We then found that TFAP2C overexpression reduced prion propagation in wild-type cells and neutralized prion accumulation in HNRNPK-suppressed cells. We conclude that TFAP2C and HNRNPK are genetic interactors controlling cell metabolism, bioenergy and prion propagation.
2025-04-01 | GSE279798 | GEO
Project description:Heterogenous Nuclear Ribonucleoprotein K (HNRNPK) is a limiting factor for prion propagation. However, little is known about the function of hnRNP_K other that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify functional epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2γ (TFAP2C) mitigated the survival of hnRNP_K-depleted LN-229 and U-251MG cells, whereas its overexpression hypersensitized cells to the loss of hnRNP_K. HNRNPK ablation induced downregulation of genes related to lipid and glucose metabolism, decreased cellular ATP and enhanced catabolism through modulation of the mTOR and AMPK pathways. Conversely, TFAP2C overexpression promoted mTOR anabolic activity, and its deletion countered the energetic crisis resulting from HNRNPK ablation. We then found that TFAP2C overexpression reduced prion propagation in wild-type cells and neutralized prion accumulation in HNRNPK-suppressed cells. We conclude that TFAP2C and HNRNPK are genetic interactors controlling cell metabolism, bioenergy and prion propagation.
2025-04-01 | GSE279797 | GEO
Project description:TFAP2C and HNRNPK control cellular bioenergetic metabolism and prion propagation [RNA-seq]
| PRJNA1174707 | ENA
Project description:DNA microarrays were used to profile gene expression in normal murine splenic cells vs. prion infected splenic cells with the aim of identifying host factors involved in prion propagation and/or useful as biomarkers for early diagnosis.
2011-07-01 | GSE17446 | 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:DNA microarrays were used to profile gene expression in normal murine splenic cells vs. prion infected splenic cells with the aim of identifying host factors involved in prion propagation and/or useful as biomarkers for early diagnosis. Two condition experiment, prion infected murine splenic cells vs. normal murine splenic cells: 4 infected biological replicates, 2 control biological replicates, 2 technical replicates (dye-swaps) for each competitive hybridization. Samples were run on 4 different arrays: MPB Murine 16K BMAP-MSV printrun 7.1 microarray MPB Murine 16K BMAP-MSV printrun 9.1 microarray MPB Murine 32K Oligo printrun 4.1 microarray Agilent 4x44K Whole Mouse Genome
2011-07-01 | E-GEOD-17446 | biostudies-arrayexpress
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214373 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214375 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214374 | GEO
Project description:Ewing sarcoma is a highly aggressive tumor characterized by a translocation between members of the FET family of RNA binding proteins and one of several ETS transcription factors, with the most common translocation being EWS-FLI1. EWS-FLI1 leads to changes in gene expression through mechanisms that are not completely understood. We performed RNA sequencing analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify novel target genes. This analysis identified lnc277 as a previously uncharacterized long non-coding RNA upregulated by EWS-FLI1 in pMPCs. Inhibiting the expression of lnc277 diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar whereas inhibiting lnc277 had no effect on other cell types tested. By analyzing gene expression after shRNA knockdown, we found that both EWS-FLI1 and lnc277 repressed many more genes that they induced and that a significant fraction of EWS-FLI1 repressed targets were also repressed by lnc277. Analysis of primary human Ewing sarcoma RNA sequencing data further supports a role for lnc277 in mediating gene repression. We identified hnRNPK as an RNA binding protein that interacts directly with lnc277. We found a significant overlap in the genes repressed by hnRNPK and those repressed by both EWS-FLI1 and lnc277, suggesting that hnRNPK participates in lnc277 mediated gene repression. Thus, lnc277 is a previously uncharacterized long non-coding RNA downstream of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes. Our studies identify a novel mechanism of oncogenesis downstream of a chromosomal translocation and underscore the importance of lncRNA-mediated gene repression as a mechanism of EWS-FLI1 transcriptional regulation. A673 Ewing cells expressing an shRNA targeting hnRNPK or control were subjected to paired end RNA sequencing and compared to shGFP control.
2014-11-01 | E-GEOD-60890 | biostudies-arrayexpress