Transcriptomics of mouse bone marrow erythropoiesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226078 | GEO | 2024/11/15
REPOSITORIES: GEO
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Project description:Ammonia is a toxic by-product of metabolism that causes cellular stress. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism that facilitate survival against toxicity have yet to be identified. We demonstrated that hypoxia-inducible factor-1α (HIF-1α) is stabilised and activated by ammonia stress. HIF-1α activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation and glutamine-dependent metabolism under ammonia stress in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1α counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1α contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.
2017-11-22 | GSE107251 | GEO
Project description:The structural-functional organization of ammonia and glutamine metabolism in the liver acinus involves highly specialized hepatocyte subpopulations such as glutamine producing perivenous scavenger cells. However, it is still unclear whether this cell population is homogeneous and involves further subpopulations. This was investigated in the present study by proteome profiling of periportal glutamine synthetase-negative hepatocytes and perivenous glutamine synthetase (GS) expressing scavenger cells isolated from mouse and rat liver. Apart from established markers of GS+ hepatocytes such as glutamate transporter 1 (GLT1), ornithine aminotransferase (OAT) or ammonium transporter Rh type B (RHBG), we identified novel scavenger cell-specific proteins such as the basal transcription factor 3 (BTF3) and the heat-shock protein 25 (HSP25). Interestingly, BTF3 and HSP25 were heterogeneously distributed among GS+ hepatocytes as shown by immunofluorescence analyses in mouse, rat and human liver slices. Feeding experiments showed that RHBG but not GS protein levels were increased in the liver of mice fed with a high protein diet compared to standard chow. While the spatial distribution of GS and carbamoylphosphate synthetase-1 (CPS1) was not affected, periportal areas constituted by GLS2 positive hepatocytes were enlarged or reduced in response to high or low protein diet, respectively. The data suggest that the population of perivenous GS+ scavenger cells is heterogeneous and not uniform as previously suggested which may reflect a functional heterogeneity, possibly relevant for liver regeneration.
2021-08-05 | PXD023561 | Pride
Project description:The malate shuttle is traditionally known to maintain the NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions was unknown. Here we show that chronic viral infections induced the expression of GOT1, the key enzyme in the malate shuttle, in CD8+ T cells. Got1 deficiency indeed decreased the NAD+/NADH ratio and dampened antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore antiviral T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate and led to toxic ammonia accumulation in CD8+ T cells. Supplementation with 2-ketoglutarate assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. This study suggests that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH ratio, but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infections.
2023-09-01 | GSE220876 | GEO
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism.
2012-07-22 | GSE35701 | GEO
Project description:The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism.
2012-07-22 | GSE35703 | GEO
Project description:Metabolic pathways driving differentiation into nephron progenitor cells (NPCs) and renal organoids from the pluripotency stage remain poorly understood. In this study, we systematically performed comprehensive metabolite and transcriptome profiling of human pluripotent stem cells (hPSCs) during differentiation into NPCs and further into multicellular organoids. We found activation of distinct metabolic pathways during early-stage progression from hPSCs to NPCs; however, later-stage differentiation from NPCs to organoids, and the intervening developmental stages between them, largely shared similar metabolic profiles. Among the pathways changing in early differentiation, the alanine-aspartate-glutamate and glutamine pathways were found to be significantly altered by both an enrichment and by pathway impact analysis. Moreover, hPSCs survived glutamine deprivation during in vitro differentiation, and NPCs were successfully generated both in the absence and presence of glutamine and glutamate. Surprisingly, glutamine deprivation resulted in enhanced maturation, by accelerating PAX8 expression, and enriching for podocytes as detected through single cell RNA-Seq analysis. Taken together, these findings highlight a critical regulatory role of glutamine metabolism in the derivation of nephron progenitor cells and renal organoids and identify a controlling metabolic pathway of early renal differentiation.
2022-06-01 | GSE128938 | GEO
Project description:Metabolic pathways driving differentiation into nephron progenitor cells (NPCs) and renal organoids from the pluripotency stage remain poorly understood. In this study, we systematically performed comprehensive metabolite and transcriptome profiling of human pluripotent stem cells (hPSCs) during differentiation into NPCs and further into multicellular organoids. We found activation of distinct metabolic pathways during early-stage progression from hPSCs to NPCs; however, later-stage differentiation from NPCs to organoids, and the intervening developmental stages between them, largely shared similar metabolic profiles. Among the pathways changing in early differentiation, the alanine-aspartate-glutamate and glutamine pathways were found to be significantly altered by both an enrichment and by pathway impact analysis. Moreover, hPSCs survived glutamine deprivation during in vitro differentiation, and NPCs were successfully generated both in the absence and presence of glutamine and glutamate. Surprisingly, glutamine deprivation resulted in enhanced maturation, by accelerating PAX8 expression, and enriching for podocytes as detected through single cell RNA-Seq analysis. Taken together, these findings highlight a critical regulatory role of glutamine metabolism in the derivation of nephron progenitor cells and renal organoids and identify a controlling metabolic pathway of early renal differentiation.
2022-06-01 | GSE128937 | GEO
Project description:Rice grown in paddy fields prefers to use ammonium ions as a major source of inorganic nitrogen. Glutamine synthetase (GS) catalyzes the conversion of ammonium ions to glutamine. In three cytosolic GS in rice, OsGS1;1 has the critical role for normal growth and grain filling. To understand a role of GS1;1, we performed transcriptional profiling of wild type Nipponbare and GS1;1 mutant plants in seedling using the Agilent Rice Oligo Microarray.
2010-03-01 | GSE15122 | GEO
Project description:Physiological and molecular evidences have shown earlier that low CO2 might have been a major driving force during the evolution of C4 photosynthesis, not only being a selection pressure but also as a signaling agent. However, a mechanistic linkage between low CO2 and C4 emergence is missing. In this study, using transcriptomics study in model plant Arabidopsis thaliana, we demonstrated that under long-term low CO2 treatments, the up-regulation of C4 related genes were linked to the up-regulation of genes involved in photorespiration, nitrogen assimilation and glycolysis. Plants under low CO2 also showed altered d13C. The carbonic anhydrase (CA), phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), glutamine oxoglutarate aminotransferase (GS-GOGAT), which are required to reassimilate ammonia, were up-regulated under low CO2. Furthermore, under low CO2, genes involved in PEP regeneration from glycolysis were up-regulated while pyruvate orthophosphate dikinase (PPDK) was down-regulated, suggesting a route of PEP regeneration from glycolysis. All these results suggested that under long-term low CO2 treatment, the selection pressure to recapture the released ammonia from the increased photorespiration might have promoted the evolution of mechanisms for generation PEP from glycolysis and enhancement of enzymes catalyzing formation of oxaloacetate, one intermediate which can accept ammonia residue. These adjustments in metabolism provide a mechanistic linkage between low CO2 and evolution of C4 photosynthesis.
2016-12-31 | GSE64547 | GEO
Project description:Nitrogen assimilation in plants is a tightly regulated process that integrates developmental and environmental signals. The legume-rhizobial symbiosis results in the formation of a specialized organ called root nodule, where the rhizobia fixes atmospheric nitrogen into ammonia. Ammonia is assimilated by the plant enzyme glutamine synthetase, which is specifically inhibited by PPT. The expression of key genes related to the regulation of root nodule metabolism will likely be affected by glutamine synthetase inhibition. We used microarrays to detail the global programme of gene expression in response to Glutamine synthetase inhibition in root nodules and identified genes differentially expressed over a time course.
2012-05-09 | GSE34155 | GEO