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Autophagy maintains metabolism and functional activity of a subset of aged hematopoietic stem cells [RRBS]

ABSTRACT: Autophagy is critical for protecting HSCs from metabolic stress. Here, we used a genetic approach to inactivate autophagy in adult HSCs by deleting the Atg12 gene. We show that loss of autophagy causes accumulation of mitochondria and an oxidative phosphorylation (OXPHOS)-activated metabolic state, which drives accelerated myeloid differentiation likely through epigenetic deregulations rather than transcriptional changes, and impairs HSC self-renewal activity and regenerative potential. To determine how loss of autophagy affects DNA methylation, we conducted enhanced reduce representation bisulfite sequencing (ERRBS) of purified control and Atg12 conditional knockout HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE81720 | GEO | 2017/03/03

SECONDARY ACCESSION(S): PRJNA322387

REPOSITORIES: GEO

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Autophagy maintains metabolism and functional activity of a subset of aged hematopoietic stem cells [ERRBS]

Project description:Autophagy is critical for protecting HSCs from metabolic stress. Here, we used a genetic approach to inactivate autophagy in adult HSCs by deleting the Atg12 gene. We show that loss of autophagy causes accumulation of mitochondria and an oxidative phosphorylation (OXPHOS)-activated metabolic state, which drives accelerated myeloid differentiation likely through epigenetic deregulations rather than transcriptional changes, and impairs HSC self-renewal activity and regenerative potential.

2017-03-03 | GSE89338 | GEO

Autophagy maintains metabolism and functional activity of a subset of aged hematopoietic stem cells [gene expression]

2017-03-03 | GSE81719 | GEO

Translational control of autophagy by Orb in the Drosophila germline [mature]

Project description:Drosophila Orb, the homologue of vertebrate CPEB is a key translational regulator involved in oocyte polarity and maturation through poly(A) tail elongation of specific mRNAs. orb has also an essential function during early oogenesis which has not been addressed at the molecular level. Here, we show that orb prevents cell death during early oogenesis, thus allowing oogenesis to progress. It does so through the repression of autophagy, by directly repressing, together with the CCR4 deadenylase, the translation of Autophagy-specific gene 12 (Atg12) mRNA. Autophagy and cell death observed in orb mutant ovaries are reduced by decreasing Atg12 or other Atg mRNA levels. These results reveal a role of Orb in translational repression and identify autophagy as an essential pathway regulated by Orb during early oogenesis. Importantly, they also establish translational regulation as a major mode of control of autophagy, a key process in cell homeostasis in response to environmental cues. Orb RIP-chip vs mock IP on ovaries from mature 3-5 day old females.

2016-07-03 | E-GEOD-74475 | biostudies-arrayexpress

Translational control of autophagy by Orb in the Drosophila germline [early]

2016-07-03 | E-GEOD-74474 | biostudies-arrayexpress

Context-Dependent Modification of PFKFB3 in Hematopoietic Stem Cells Promotes Anaerobic Glycolysis and Ensures Stress Hematopoiesis

Project description:Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in HSCs and elucidate their regulatory mechanisms. Through quantitative13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of adenosine triphosphate (ATP) levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression ofPfkfb3induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss ofPfkfb3suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.

2024-04-03 | GSE260765 | GEO

Mitochondrial respiration maintains autophagy to support stress resistance in quiescent cells

Project description:Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP and is required for pyrimidine nucleotide synthesis during proliferation. In contrast, the role of OXPHOS in post-mitotic cells, beyond its contribution to ATP production, is less understood. Here, we show that in non-proliferating cells, OXPHOS ensures protection against oxidative stress by sustaining autophagy. Autophagy is suppressed and oxidative stress resistance is compromised in OXPHOS-deficient non-proliferating cells in vitro and in TFAM knockout mice in vivo, while attenuation of autophagy in OXPHOS-functional cells phenocopies the effects of OXPHOS deficiency. Mechanistically, the regulation of the autophagy / stress response by OXPHOS does not require changes in gene expression, AMPK/mTOR1/ULK1 signaling or NADH levels. Instead, OXPHOS maintains ROS levels to prevent activation of ATG4, a ROS-activated inhibitor of autophagy. We propose that protection against oxidative stress via the ROS-ATG4 axis is a novel function of mitochondrial respiration in non-proliferating cells that may have consequences for cancer therapy and beyond.

2022-01-07 | GSE146025 | GEO

Translational control of autophagy by Orb in the Drosophila germline [mature]

2016-01-01 | GSE74475 | GEO

Translational control of autophagy by Orb in the Drosophila germline [early]

2016-01-01 | GSE74474 | GEO

Maize seed proteome of autophagy deficient plants throughout development

Project description:Autophagy or ‘self-eating’ is a conserved and essential route for recycling intracellular constituents in eukaryotes. For plants, autophagy supports robust crop performance by regulating traits such as nitrogen-use efficiency, carbon allocation, reproduction, grain fill, and protection against various environmental stresses. To define the autophagic mechanisms underlining nutrient partitioning, which are used to sustain plant fitness during rapid growth of sink tissues, we applied a comprehensive multi-omic approach using maize (Zea mays) mutants lacking the core autophagy component ATG12. A sink tissue of particular interest are seeds, which require massive investments of fixed carbon for development. The transcriptome, proteome, metabolome, and ionome of developing seeds from atg12 mutants at 8 and 18 days after pollination (DAP) were analyzed. Developing atg12 seeds exhibited pronounce transcriptional reprogramming at 8 DAP, which may contribute to the observed hyperaccumulation of proteins, metabolites, and ions at 18 DAP. Collectively, this multi-omic approach should provide new perspectives into the adaptive role(s) of autophagy in coordinating nutrient allocation.

2023-03-10 | PXD022863 | Pride

Functional Characterisation of the Ubiquitin-like Core Autophagy Protein ATG12 in Dictyostelium discoideum

Project description:Purpose: First global survey of the transcriptome in autophagy-deficient strains of D. discoideum. Results: Our RNAseq analysis of ATG12‾, ATG16‾ and ATG12‾/16‾ cells revealed major transcriptional changes in a large number of genes in comparison to AX2. Conclusions: Our study represents the first detailed analysis of the transcriptome in autophagy-deficient strains of D. discoideum. The data were generated by RNA-seq technology. The optimised data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within a cell. We conclude that RNA-seq based transcriptome characterisation would expedite genetic network analyses and permit the dissection of complex biologic functions.

2019-01-15 | GSE123780 | GEO

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