Biosynthetic plasticity enables CD8+ T cell functional resilience under nutrient stress [Atf4 & Cebpg KO RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287894 | GEO | 2026/05/05
REPOSITORIES: GEO
Similar Datasets
Project description:To maintain lineage-specific functions, cells must acquire and allocate nutrients across diverse cellular processes, even in metabolically-dysregulated environments. The mechanisms allowing CD8+ T cells to maintain immune function in perturbed environments are poorly understood. We find that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reorient translational programming, limiting nutrient demand while prioritizing stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors ATF4 and CEBPG jointly establish an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial anaplerosis. Despite diminished energetic capacity under environmental stress, this program prevents failure of central carbon metabolism, mitigating stress amplification and cellular dysfunction to potentiate anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers functional resilience to immune cells in unfavorable environments, offering novel strategies to enhance immunotherapies.
2026-05-05 | GSE287987 | GEO
Project description:Deregulated oxidative metabolism is a hallmark of leukaemia. While use of tyrosine kinase inhibitors (TKIs) such as imatinib has led to increased survival of chronic myeloid leukaemia (CML) patients, it fails to eradicate disease initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays we generated multi-omics datasets that offer unprecedented insight into nutrient fate in patient derived CML LSCs. We demonstrate that LSCs have increased glucose anaplerosis when compared to normal hematopoietic stem cells. While imatinib treatment reverses BCR-ABL-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics revealed that deregulated glucose anaplerosis is unaffected by imatinib. Encouragingly, genetic ablation of glucose anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that the clinical oral-available inhibitor MSDC-0160 targets glucose anaplerosis in robust pre-clinical CML models. Collectively these results highlight glucose anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient samples.
2023-06-27 | GSE216837 | GEO
Project description:BACKGROUND: The ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown. RESULTS: A global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation. CONCLUSIONS: Application of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-140]
2013-06-10 | E-BUGS-140 | biostudies-arrayexpress
Project description:Transcription profiling of wild type, relA-, and relA-spoT-, crp-, dksA-, rpoS-, lrp- mutant strains of E. coli starved for isoleucine Bacteria comprehensively reorganize their global gene expression when faced with nutrient exhaustion. In Escherichia coli and other free-living bacteria, the alarmone ppGpp facilitates this massive response by directly or indirectly coordinating the down-regulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation likely requires the cooperative activities of many different genetic regulators, yet the structure of the transcription network below the level of ppGpp remains poorly defined. Using isoleucine starvation as an experimental model system for amino acid starvation, we identified genes that required ppGpp, Lrp, and RpoS for their induction. Surprisingly, despite the fact that the overwhelming majority of genes controlled by Lrp and RpoS required ppGpp for their activation, we found that these two regulons were not induced simultaneously. The data reported here suggest that metabolic genes, such as those of the Lrp regulon, require only a low basal level of ppGpp for their efficient induction. In contrast, the RpoS-dependent general stress response is not robustly induced until relatively high levels of ppGpp accumulate. Here we describe a data-driven conceptual model that explains how bacterial cells allocate transcriptional resources between metabolic and stress survival processes by discretely tuning regulatory activities to a central indicator of cellular physiology. The regulatory structure that emerges is consistent with a rheostatic model of the stringent response that allows cells to efficiently adapt to a wide range of nutritional environments. Keywords: genetic modification design; stress response; isoleucine starvation
2008-04-08 | GSE11087 | GEO
Project description:Metabolic flexibility, or the ability to adapt to environmental fluctuations, is key to the survival and growth of all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although cancers are known to display metabolic dependencies that can be targeted for therapy. Here, we combine systematic nutrient and genome-wide CRISPR/Cas9 screening to provide a comprehensive map of the signaling and metabolic pathways that support cell proliferation in glutamine-limited conditions. We focus on pyruvate anaplerosis and discover a mechanism by which the tumor suppressor FBXW7 controls a MYC-dependent cluster of epigenetic repressors that bind the pyruvate carboxylase (PC) promoter, leading to histone deacetylation, reduced PC expression and glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility, and on the nutrients and pathways involved in glutamine dependency, a hallmark of several cancers.
2026-01-30 | PXD057389 | Pride
Project description:CTP synthase (CTPS) forms compartmentalized filaments in response to substrate availability and environmental nutrient status. However, the physiological role of filaments and mechanisms for filament assembly are not well understood. Here, we provide evidence that CTPS forms filaments in response to histidine influx during glutamine starvation. CTPS protein levels remained stable in the presence of histidine during nutrient deprivation, followed by rapid cell growth following nutrient replenishment. Tetramer conformation-based filament formation restricted CTPS enzyme activity duringnutrient deprivation. Furthermore, we demonstrated that filament formation controlled at two levels. Starvation stress/glutamine deficiency activates the GCN2/ATF4/MTHFD2 axis to accelerate the folate cycle in mitochondria for energy homeostasis. In addition, histidine promotes re-methylation of homocysteine by donating one-carbon to the cytosolic folate cycle. CTPS filament formation induced by histidine-mediated methylation maybe a strategy usedby cancer cells to maintain homeostasis and ensure a growth advantage in adverse environments.
2018-08-29 | GSE105251 | GEO
Project description:Transcription profiling of wild type, relA-, and relA-spoT-, crp-, dksA-, rpoS-, lrp- mutant strains of E. coli starved for isoleucine Bacteria comprehensively reorganize their global gene expression when faced with nutrient exhaustion. In Escherichia coli and other free-living bacteria, the alarmone ppGpp facilitates this massive response by directly or indirectly coordinating the down-regulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation likely requires the cooperative activities of many different genetic regulators, yet the structure of the transcription network below the level of ppGpp remains poorly defined. Using isoleucine starvation as an experimental model system for amino acid starvation, we identified genes that required ppGpp, Lrp, and RpoS for their induction. Surprisingly, despite the fact that the overwhelming majority of genes controlled by Lrp and RpoS required ppGpp for their activation, we found that these two regulons were not induced simultaneously. The data reported here suggest that metabolic genes, such as those of the Lrp regulon, require only a low basal level of ppGpp for their efficient induction. In contrast, the RpoS-dependent general stress response is not robustly induced until relatively high levels of ppGpp accumulate. Here we describe a data-driven conceptual model that explains how bacterial cells allocate transcriptional resources between metabolic and stress survival processes by discretely tuning regulatory activities to a central indicator of cellular physiology. The regulatory structure that emerges is consistent with a rheostatic model of the stringent response that allows cells to efficiently adapt to a wide range of nutritional environments. Keywords: genetic modification design; stress response; isoleucine starvation Two experiments were run. First experiment: WT and several mutant strains were starved for isoleucine (exhaustion of 60 uM ile). 40 minutes after starvation, RNA was extracted. All samples were compared to RNA from rapidly growing WT cells in identical medium replete with isoleucine (400 uM). 16 samples were hybridized: duplicates of 8 strains/conditions. Wildtype in log phase (OD = 0.4) with replete ile was control for ile starved samples. Second experiment: WT strain was starved for isoleucine (exhaustion of 60 uM ile). RNA was extracted at 12 timepoints as the cells entered stationary phase. All samples were compared to RNA from rapidly growing WT cells in identical medium replete with isoleucine (400 uM). 14 samples were hybridized: duplicates of the control condition and single timepoints during starvation. Wildtype in log phase (OD = 0.4) with replete ile was control for ile starved samples.
2008-04-08 | E-GEOD-11087 | biostudies-arrayexpress
Project description:Thermotolerance of fungal pathogens is critical for host adaptation, and most fungi cannot survive at mammalian body temperatures, making heat stress a key host defense. Cryptococcus neoformans, a leading cause of fungal meningitis, must overcome host fever and nutrient limitation to establish infection. However, the metabolic adaptations enabling C. neoformans to overcome this barrier remain unclear. Here, we investigated the role of a protein deacetylase Dac6 in C. neoformans thermotolerance and pathogenicity, focusing on its metabolic regulation under heat stress. We found that Dac6 is a thermotolerance regulator, distinct from its yeast homolog Rpd3, and its expression correlates with heat resistance in clinical strains. Multi-omics analyses reveal that Dac6 modulates histone acetylation and gene expression to reprogram amino acid metabolism under heat stress, particularly lysine and threonine. Notably, lysine and threonine are also the major altered metabolites in host during cryptococcal infection, and Dac6 deletion impaired fungal utilization of lysine and threonine under heat stress in vitro and in vivo. Consequently, Dac6 deficiency leads to reduced lung and brain colonization, and attenuated virulence in mice. Our study uncovers a metabolic adaptation mechanism by which Dac6 links nutrient utilization to thermotolerance and virulence, providing new insights into fungal survival strategies in high-temperature host environments.
2025-11-25 | GSE302506 | GEO
Project description:Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analysing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries.
2025-02-03 | GSE248966 | GEO
Project description:Candida albicans biofilms form complex structures that shield the fungus from antifungal agents and host immune responses, which is particularly problematic for the treatment of severe candidiasis. The increasing thickness and formation of hyphal networks of growing biofilms result in nutrient and gas shifts that lead to sequential metabolic rearrangements. This study provides very comprehensive insights into the molecular and metabolic mechanisms of C. albicans biofilm maturation by combining three state-of-the-art omics techniques. Adaptive nutrient and stress responses enabled wild type biofilms to mature in an increasingly nutrient- and oxygen-limited environment. C. albicans biofilms lacking Stp2, a transcriptional regulator of amino acid uptake, underwent extensive transcriptional changes resulting in metabolic adaptations such as broad restructuring of nitrogen metabolism, glucose uptake, and acquisition of alternative nutrients. This finding underscores the indispensable need for amino acid supply during biofilm development and emphasizes the tremendous metabolic flexibility to adapt to changing environments that have made C. albicans a successful opportunistic pathogen.
2022-10-13 | PXD026449 | Pride