Mus musculus
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ABSTRACT:
PROVIDER: PRJNA258380 | ENA |
REPOSITORIES: ENA
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Project description:Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway, which is the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 as a microRNA capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain and greatly reduced protein aggregates in a lentivirus model of polyglutamine disease, establishing the physiological relevance of let-7 for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond the CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms. Using sets of wild-type C57BL/6J mice, we established primary cortical neuron cultures from P0 littermates, and cultured these neurons (n = 3 / set) in CM or NLM for 4 hrs.
2015-08-03 | E-GEOD-60452 | biostudies-arrayexpress
Project description:Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway, which is the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 as a microRNA capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain and greatly reduced protein aggregates in a lentivirus model of polyglutamine disease, establishing the physiological relevance of let-7 for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond the CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.
2019-08-01 | GSE60848 | GEO
Project description:Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway, which is the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 as a microRNA capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain and greatly reduced protein aggregates in a lentivirus model of polyglutamine disease, establishing the physiological relevance of let-7 for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond the CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.
2015-08-03 | GSE60452 | GEO
Project description:Autophagy is a conserved process of cellular self-digestion that promotes survival during nutrient stress. In yeast, methionine starvation is sufficient to induce autophagy. One pathway of autophagy induction is governed by the SEACIT complex, which regulates TORC1 activity in response to amino acids through the Rag GTPases Gtr1 and Gtr2 This work identifies an unexpected yet critical role for Xrn1 in nutrient sensing and growth control that extends beyond its canonical housekeeping function in RNA degradation and indicates an avenue for RNA metabolism to function in amino acid signaling into TORC1.
2023-10-19 | GSE226779 | GEO
Project description:Metabolic reprogramming sustains cancer cell anabolism, and MYC oncoproteins control many aspects of this response. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Surprisingly, here we report the autophagy-lysosomal pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eµ-Myc transgenic mice, and in MYC-driven human Burkitt lymphoma. Myc suppresses autophagy by antagonizing expression and function of TFEB, a master regulator of autophagy/lysosome genes. Notably, compensatory mechanisms that sustain AA pools in MYC-expressing B cells include marked increases in AA transport and coordinate induction of the proteasome. Finally, reactivation of the autophagy-lysosomal pathway by constitutively active TFEB disables the malignant state, by perturbing mitochondrial functions and disrupting proteasome activity, amino acid transport, and disrupts amino acid and nucleotide metabolism, leading to growth arrest and apoptosis. This scenario provides therapeutic opportunities that disable MYC-driven tumorigenesis, including AA restriction and treatment with proteasome inhibitors.
2022-02-27 | GSE153570 | GEO
Project description:Circadian clocks are evolved to adapt to the daily environment changes under different conditions. The ability to maintain circadian clock functions in response to various stress and perturbations is important for organismal fitness. Here, we show that the nutrient sensing GCN2 signaling pathway is required for robust circadian clock function under amino acid starvation in Neurospora. The deletion of GCN2 pathway components disrupts rhythmic transcription of clock gene frq by suppressing WC complex binding at the frq promoter due to its reduced histone H3 acetylation levels. Under amino acid starvation, the activation of GCN2 kinase and its downstream transcription factor CPC-1 establish a proper chromatin state at the frq promoter by recruiting the histone acetyltransferase GCN-5. The arrhythmic phenotype of the GCN2 kinase mutants under amino acid starvation can be rescued by inhibiting histone deacetylation. Finally, genome-wide transcriptional analysis indicates that the GCN2 signaling pathway maintains robust rhythmic expression of metabolic genes under amino acid starvation. Together, these results uncover an essential role of GCN2 signaling pathway in maintaining robust circadian clock function in response to amino acid starvation and the importance of histone acetylation at the frq locus in rhythmic gene expression.
2023-05-08 | GSE220169 | GEO
Project description:Autophagy, a catabolic process to remove unnecessary or dysfunctional cells, is triggered by various signals including nutrient starvation. Depending on the type of the nutrient deficiency, diverse sensing mechanisms and pathways are used for autophagy, suggesting subsequent nutrient dependent transcriptional regulation. Still, however, our knowledge about nutrient specific transcriptional regulation during autophagy is limited. To understand nutrient type dependent transcriptional mechanisms during autophagy, we performed single cell RNA sequencing (scRNAseq) for the mouse embryonic fibroblasts (MEFs) before and after applying glucose- (GS) as well as amino acid starvation (AAS). Trajectory analysis using scRNAseq identified sequential induction of potential transcriptional regulators for each deficiency condition. Gene regulatory rules inferred using TENET newly identified CCAAT/enhancer binding protein γ (C/EBPγ) regulates autophagy processes specifically to AAS condition. Strikingly, knockdown of C/EBPγ attenuated the autophagic process only in the AAS condition. Cell biological and biochemical studies validated that C/EBPγ plays a switching role for ATF4 to activate autophagy genes under AAS, but not under GS. Together, our data identified C/EBPγ as a previously unidentified key regulator under amino acid starvation-induced autophagy.
2022-04-04 | GSE199923 | GEO
Project description:Autophagy, a catabolic process to remove unnecessary or dysfunctional cells, is triggered by various signals including nutrient starvation. Depending on the type of the nutrient deficiency, diverse sensing mechanisms and pathways are used for autophagy, suggesting subsequent nutrient dependent transcriptional regulation. Still, however, our knowledge about nutrient specific transcriptional regulation during autophagy is limited. To understand nutrient type dependent transcriptional mechanisms during autophagy, we performed single cell RNA sequencing (scRNAseq) for the mouse embryonic fibroblasts (MEFs) before and after applying glucose- (GS) as well as amino acid starvation (AAS). Trajectory analysis using scRNAseq identified sequential induction of potential transcriptional regulators for each deficiency condition. Gene regulatory rules inferred using TENET newly identified CCAAT/enhancer binding protein γ (C/EBPγ) regulates autophagy processes specifically to AAS condition. Strikingly, knockdown of C/EBPγ attenuated the autophagic process only in the AAS condition. Cell biological and biochemical studies validated that C/EBPγ plays a switching role for ATF4 to activate autophagy genes under AAS, but not under GS. Together, our data identified C/EBPγ as a previously unidentified key regulator under amino acid starvation-induced autophagy.
2021-12-01 | GSE189710 | GEO
Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina
2014-09-27 | E-GEOD-61817 | biostudies-arrayexpress
Project description:The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response, but also triggers ferroptosis, a non-apoptotic cell death. Here we report that, unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent CysRx that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic perturbation.
2023-08-30 | GSE237928 | GEO