A genome-wide CRISPR screen identifies mediators of ferroptosis sensitivity in polyunsaturated fatty acid-treated cells
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ABSTRACT:
PROVIDER: PRJNA542171 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9036830.fastq.gz | Fastqsanger.gz | |||
| SRR9036840.fastq.gz | Fastqsanger.gz | |||
| SRR9036831.fastq.gz | Fastqsanger.gz | |||
| SRR9036841.fastq.gz | Fastqsanger.gz | |||
| SRR9036832.fastq.gz | Fastqsanger.gz |
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Project description:Polyunsaturated fatty acids (PUFA) sensitize cells to ferroptotic cell death. In the study associated with this dataset, we used UACC257 as a model cell line (intrinsically resistant to ferroptosis) induced to be sensitive to ferroptosis with different PUFAs. We performed genome-wide CRISPR knockout screen to identify genes that mediate the sensitivity to ML210, a selective inhibitor of glutathione peroxidase 4 (GPX4) and a potent inducer of ferroptotic cell death. We identified cytochrome P450 oxidoreductase (POR, CYPOR) as a key player required for ferroptotic cell death among other genes.
2020-01-01 | GSE130982 | GEO
Project description:Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCC tumors are distinguished by aberrant lipid and glycogen accumulation and are inherently refractory to a broad range of anti-cancer therapies. In the study associated with this dataset, we identified an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCC cells. However, the mediators of this sensitivity to ferroptosis are unknown. Here we perform a genome-wide CRISPR screen to identify genes that mediate the sensitivity to ML210, a selective inhibitor of glutathione peroxidase 4 (GPX4) and a potent inducer of ferroptotic cell death in 786-O, a clear-cell renal cell carcinoma cell line.
2019-03-04 | GSE126696 | GEO
Project description:A genome-wide CRISPR screen identifies mediators of ferroptosis sensitivity in clear-cell carcinomas
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Project description:Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.
2020-11-13 | PXD016276 | Pride
Project description:Genome-wide CRISPR screens were performed in Huh-7 hepatoma cell line to identify genes regulating ferroptosis sensitivity. Huh-7 cells were transduced with Human GeCKO library and selected by RSL-3.
2023-04-17 | GSE228883 | GEO
Project description:Phospholipids containing polyunsaturated fatty acyl tails (PL-PUFAs) are susceptible to lipid peroxidation by reactive oxygen species, lipoxygenases, and radical species. The accumulation of peroxidized lipids in cell membranes overwhelms endogenous lipid repair processes and triggers ferroptosis. We discovered that phospholipids with both PUFA tails (PL-PUFA2s) acted as key drivers of ferroptosis in numerous cancer cell lines, compared with phospholipids with a single PUFA tail (PL-PUFA1s), which were substantially less capable of inducing ferroptosis. We found that exogenously supplied phosphatidylcholine with two PUFA tails (PC-PUFA2) was rapidly incorporated into and remodeled membranes in cell lipids. Moreover, PC-PUFA2s were enriched upon free PUFA treatment, suggesting a key role in driving free-PUFA-initiated ferroptosis. We examined the protein-binding profile of PC-PUFA2 and found a specific interaction with the mitochondrial electron transport chain complex I. We confirmed that PC-PUFA2s accumulate in mitochondria and induce production of mitochondrial ROS, which then spread to the endoplasmic reticulum. Depletion of mitochondria through mitophagy eliminated the enhanced potency of PC-PUFA2s over PC-PUFA1s in driving ferroptosis, consistent with mitochondria being the key target of PC-PUFA2s. PC-PUFA2s are thus important lipid markers and drivers of ferroptosis and may serve as future biomarkers and therapeutic targets for modulating ferroptosis in pathological contexts.
2025-05-06 | PXD041993 | Pride
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array randomized crossover dietary intervention study
2012-02-21 | E-GEOD-31901 | biostudies-arrayexpress
Project description:A genome-wide CRISPR screen for genes regulating ferroptosis sensitivity
| PRJNA951777 | ENA
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array
2012-02-21 | GSE31901 | GEO
Project description:Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution.
2017-06-01 | GSE86384 | GEO