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Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

ABSTRACT: Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

PROVIDER: PRJNA800758 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17762734_1.fastq.gz	Fastqsanger.gz
	SRR17762734_2.fastq.gz	Fastqsanger.gz
	SRR17762735_1.fastq.gz	Fastqsanger.gz
	SRR17762735_2.fastq.gz	Fastqsanger.gz
	SRR17762736_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

Project description:We analyzed the transcriptomes of Wild-type and GCN2-deficient mouse embryonic stem cells after 3h of arginine or leucine starvation.

2024-01-01 | GSE195470 | GEO

GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation

Project description:Background: Arginine deprivation was shown previously to inhibit retinoblastoma cell proliferation and induce cell death in vitro. However, the mechanisms by which retinoblastoma cells respond to arginine deprivation remain to be elucidated. Methods: Human derived retinoblastoma cell lines Y79 and WERI-Rb-1 were exposed to arginine depletion, and the effects on inhibiting cell growth and survival were evaluated. The study investigated potential mechanisms, including autophagy, cell cycle arrest, and apoptosis. Moreover, the roles of GCN2 and mTOR signaling pathways in these processes were examined. Results: We demonstrated that arginine deprivation effectively inhibited the growth of retinoblastoma cells in vitro. This treatment caused an increase in autophagic response. Additionally, we found that prolonged arginine shortage induced G2 cell cycle arrest and was accompanied by an increase in early apoptotic cells. Importantly, arginine depletion also caused an activation of GCN2 and an inhibition of mTOR signaling. We also discovered that the activation of SLC7A11 was regulated by GCN2 upon arginine deprivation. Knockdown of SLC7A11 rendered retinoblastoma cells partially resistant to arginine deprivation. Furthermore, we found that knockdown of GCN2 led to a decrease in autophagic response in WERI-Rb-1 cells and arrested more cells in S phase, which was accompanied by fewer apoptotic cells. Moreover, knockdown of GCN2 caused constant expression of ATF4, phosphorylation of 70S6K, and 4E-BP1 regardless of arginine deprivation. Conclusions: Collectively, our findings suggest that the GCN2-SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.

2024-10-28 | GSE278276 | GEO

Transcriptomic analysis of the impact of a short-term leucine deprivation and evaluation of GCN2 involvement in induced gene differential expression in human primary T cells

Project description:We previously demonstrated the proof of concept for the functionality of the NUTRIREG system in T cells. This technology allows for the induction of transgene expression following the consumption of a diet deficient in an essential amino acid, by activating the GCN2-ATF4 signaling pathway. To utilize the NUTRIREG technology for therapeutic purposes in cell therapy with short-term EAA deprivation, we explored the general impact of 6-hour leucine deprivation on primary activated human T cells using RNA-seq technology. We identified 3,431 differentially expressed genes (adjusted p-value < 0.05) between T cells cultured in control media and those cultured in leucine-deprived media for 6 hours. Gene Set Enrichment Analysis revealed that "TNFα signaling via NFκB", "interferon-γ response", and "unfolded protein response" gene sets were positively enriched, while "mTORC1 signaling", "Myc targets", and "oxidative phosphorylation" gene sets were negatively enriched. T cells were cultured with or without a GCN2 inhibitor, which allowed us to assess the involvement of GCN2 kinase in differential gene expression during the 6-hour leucine deprivation. We found that 59% of the differentially expressed genes (DEGs) in our dataset were dependent on GCN2 kinase (n=2028), with 1,140 up-regulated and 888 down-regulated GCN2-dependent genes.

2025-01-20 | GSE279263 | GEO

GCN2 adapts the proteome to scavenging-dependent growth

Project description:We report the transcriptional and translational changes that occur upon leucine deprivation +/- GCN2.

2020-05-25 | GSE151118 | GEO

GCN2 Adapts Protein Synthesis to Scavenging-Dependent Growth

Project description:Compared protein synthesis in Gcn2 WT vs Gcn2 KO murine PDAC cells (KRPC) in amino acid-replete or leucine-free media.

2022-10-13 | PXD028143 | Pride

Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine

Project description:Amino acid availability regulates translation through the action of the GCN2 and mTORC1 pathways. Low amino acids activate the eIF2α kinase GCN2 through binding of uncharged tRNAs to a histidyl-tRNA synthetase−related regulatory domain. Once activated GCN2 phosphorylates eIF2α, inhibiting ternary complex formation and translation initiation. Recent studies show that mTORC1 is particularly sensitive to arginine and leucine status, with a deprivation of these amino acids leading to a strong inhibition of mTORC1 that prevents the phosphorylation and inactivation of the translational repressor 4EBP1. Though amino acids are known regulators of translation, the effects that deficiencies of specific amino acids have on translation have yet to be determined. We demonstrate that deprivation of leucine or methionine results in large inhibitory effects on translation initiation and on polysome formation that are not replicated by overexpressing non-phosphorylatable 4EBP1 or a phosphomimetic eIF2α. Our results demonstrate that a lack of either leucine or methionine has a major impact on mRNA translation, though they act by quite different mechanisms. Leucine deprivation appears to primarily inhibit ribosome loading, whereas methionine deprivation appears to primarily impair start site recognition. These data point to a unique regulatory effect that methionine status has on translation initiation.

2018-04-04 | GSE112643 | GEO

Transcription profiling by array of cells starved of leucine in the presence or absence of a dominant negative HSF1 mutant (dnHSF1, HSF379).

Project description:Cells were starved for leucine in the presence or absence of a dominant negative HSF1 mutant (dnHSF1, HSF379). Changes in transcriptome relative to cells cultured with leucine were determined. The experiment shows the effect of dnHSF on the amino acid starvation response.

2012-12-11 | E-MEXP-3563 | biostudies-arrayexpress

Ribosome profiling of control and leucine-starved SUM159 cells

Project description:SUM159 cells were either grown in standard medium or in leucine-depleted medium, or in medium containing 20% of the standard concentration of leucine

2017-07-27 | GSE69921 | GEO

GCN2 suppresses TOP mRNA translation via LARP1

Project description:La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine tract (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5’TOP motif, resulting in the displacement of the eIF4E complex from TOP mRNAs. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. GCN2 inhibits TOP mRNA translation via ATF4-dependent transcriptional induction of LARP1 mRNAs and GCN1-mediated recruitment of LARP1 to stalled ribosomes. We performed ATF4 ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-08-31 | GSE166590 | GEO

Translational control through differential ribosome pausing during amino acid limitation in mammalian cells

Project description:Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that limitation for the amino acid arginine causes a selective loss of tRNA charging, which regulates translation through ribosome pausing at two of six arginine codons. Interestingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation led to loss of arginine tRNA charging and ribosome pausing. Codon-specific ribosome pausing decreased protein production and triggered premature ribosome termination without significantly reducing mRNA levels. Together, our results suggest that amino acids which are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on synonymous codon usage.

2018-07-19 | GSE113751 | GEO

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