MTOR-dependent translation amplifies microglia priming in ageing
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ABSTRACT:
PROVIDER: PRJNA658992 | ENA |
REPOSITORIES: ENA
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Project description:Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as cytokine protein levels. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1 and increased 4EBP1 expression, resulting in decreased binding of EIF4E to EIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in ageing and neurodegeneration.
2021-07-30 | GSE156762 | GEO
Project description: Not available
| S-EPMC7773382 | biostudies-literature
Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation
2015-01-31 | E-GEOD-63022 | biostudies-arrayexpress
Project description:Forkhead Box O (FOXO) transcription factors are versatile players in diverse cellular processes, affecting tumorigenesis, metabolism, stem cell maintenance and lifespan. To understand the transcriptional output of FOXO3 activation, we investigate features that define the subset of enhancer binding events that actually contribute to gene regulation. We show FOXO3 transcriptional output is determined by the amount of bound FOXO3, which in turn is determined by motif presence, pre-existing enhancer activity and accessibility. In this manner, FOXO3 amplifies pre-existing levels of activity marks and potentiates enhancer RNA transcription. We conclude that not only enhancer presence and sequence content, but also the pre-existing activity dictates FOXO3 binding and transcriptional output. Considering the flexible and cell type specific nature of regulatory regions and their activity, our observations provide a novel explanation for the diversity in FOXO transcriptional programs and introduce chromatin context as a new player in the regulation of FOXO activity in ageing and disease. Examination of histone modifications and transcriptome changes upon FOXO activation
2013-11-26 | E-GEOD-50243 | biostudies-arrayexpress
Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory.
2015-01-31 | GSE63022 | GEO
Project description:Our strategy was to manipulate mTOR signaling in vivo, then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the non-proliferative growth model of refeeding after a period of fasting, and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from pre-term fetal rats (embryonic day 19-20) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling.
2015-06-01 | GSE67022 | GEO
Project description:Cancer incidence escalates exponentially with advancing age, the mechanism of which remains obscure. Here we built up a chronological molecular clock at the single cell level for the mammary stem cell enriched population to depict the physiological ageing dynamics. We found the mammary ageing process was asynchronous and progressive, determined by the relative proportions of four distinct cellular states. The mammary ageing was initiated by a light senescence state with elevated NFkb, P53 signals, followed by a deep senescence state with reduced NFkb, P53 and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotency activities succumb to cancer predisposition. Both of these senescence programs were regulated by a master mammary stem cell factor Bcl11b through modulation of multiple stress, longevity and pluripotency associated pathways. Depletion of Bcl11b triggered morphological, functional and molecular ageing-like phenotypes, and drastically enhanced DMBA-induced tumor formation. We further screened out a drug TPCA-1 that can elevate Bcl11b activity, rejuvenate mammary cells transcriptomically and significantly reduce the ageing-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell ageing and elucidated the regulatory network bridging mammary ageing and cancer predisposition that can be modulated to control the cancer initiation, which has potential implications in management of cancer prevalence.
2024-04-02 | GSE195647 | GEO
Project description:Rapamycin is a naturally derived macrolide antibiotic that demonstrates immunosuppressive, chemotherapeutic, and anti-ageing effects in model organisms and humans. Importantly, Rapamycin and its analogues are currently used in the clinic against various cancers and neurological disorders. Although Rapamycin is widely perceived as a specific allosteric inhibitor of mTOR (mechanistic target of rapamycin), the master regulator of cellular and organismal physiology, its specificity has not been thoroughly evaluated so far. In fact, previous studies in cells and in mice suggested that Rapamycin may be also acting independently from mTOR to influence various cellular functions. Here, we generated a gene-edited cell line, expressing a Rapamycin-resistant mTOR mutant (mTORRR), and assessed the effects of Rapamycin treatment on the transcriptome and proteome of control and mTORRR-expressing cells. Our data reveal a striking specificity of Rapamycin towards mTOR, demonstrated by virtually no changes in mRNA or protein levels in Rapamycin-treated mTORRR cells, even following prolonged drug treatment. Overall, this study provides the first comprehensive and conclusive assessment of Rapamycin’s specificity, with important potential implications for ageing research and therapeutics.
2023-05-24 | PXD038051 | Pride
Project description:mTOR regulates mRNA translation. Whereas ribosome-profiling suggested that mTOR exclusively stimulates translation of TOP (containing a 5â-terminal oligopyrimidine [5âTOP] motif) and TOP-like mRNAs, polysome-profiling implied that mTOR also modulates translation of non-TOP mRNAs. We show that ribosome-, but not polysome-profiling, is biased towards identification of TOP mRNAs as differentially translated while obscuring detection of changes in non-TOP mRNA translation. Transcription start site profiling by Nano-Cap Analysis of Gene Expression (nanoCAGE) revealed that many mTOR-sensitive mRNAs do not have 5âTOP motifs. Moreover, nanoCAGE showed that 5â UTR features distinguish two functionally and translationally distinct subsets of mTOR-sensitive mRNAs: i) those with short 5â UTRs enriched for mitochondrial functions such as respiration, that are translated in an eIF4E, but not eIF4A1-dependent manner and ii) mRNAs encoding proliferation- and survival-promoting proteins, that harbor long 5â UTRs, and require both eIF4E and eIF4A1 for their efficient translation. Selective inhibition of translation of mRNAs harboring long 5â UTRs via suppression of eIF4A leads to uncoupling of expression of proteins involved in respiration (e.g. ATP5O) from those protecting mitochondrial integrity (e.g. BCL-2) ultimately resulting in apoptosis. Conversely, simultaneous translational downregulation of both long and short 5â UTR mRNAs by mTOR inhibitors results in suppression of mitochondrial respiration and predominantly cytostatic effects. Therefore, 5â UTR features define differential modes of translation of functionally distinct mTOR-sensitive mRNAs, which explains discrepancies between the effects of mTOR and eIF4A inhibitors on neoplastic cells. Determination of 5'UTR lengths using nanoCAGE in MCF7 cells
2016-03-14 | E-GEOD-77033 | biostudies-arrayexpress