Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA747022 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15164948.fastq.gz | Fastqsanger.gz | |||
| SRR15164949.fastq.gz | Fastqsanger.gz | |||
| SRR15164950.fastq.gz | Fastqsanger.gz | |||
| SRR15164951.fastq.gz | Fastqsanger.gz | |||
| SRR15164952.fastq.gz | Fastqsanger.gz |
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Project description:The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. The mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.
2022-06-13 | PXD033122 | Pride
Project description:We show that ribosome collisions, induced by Rptor deletion or aminoacid starvation, causes a ZAK alpha mediated identity switch in intestinal stem cells by activating a more fetal-like stem cell signature. This switch also causes changes in metabolic profiles of the cells, which is heavily regulated by RNA translation efficiency of different group of metabolic genes. These observations originate from performing in vitro Riboseq and RNAseq in mouse intestinal organoids, and in vivo Riboseq in Lgr5 expressing intestinal stem cells from WT and Rptor.fl/fl mice.
2022-06-08 | GSE180208 | GEO
Project description:The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. However, the mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.
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Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
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Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
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Project description:The avian cerebellum is known for its relatively large size and high degree of development, functioning as a crucial region for multisensory integration and motor control, particularly important for flight. This study aimed to investigate changes in gene expression in the cerebellum of racing pigeons using RNA-Seq analysis. The researchers analyzed samples from 10 racing homers' cerebellums before and after a 300 km flight back to their loft. The findings revealed that flight induces ribosome impairment in the cerebellum, suggesting potential alterations in the protein synthesis machinery due to prolonged flight activity as response to stress and maintain homeostasis.
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Project description:mRNA translation is a highly dynamic process that has been shown to modulate cell adaptation to stress conditions. Upon ribosome impairment, ZAKα affects the metabolic profile of intestinal cells, however the mechanism by which this is promoted is still unclear. Here, we identified the nascent polypeptide-associated complex (NAC) as a central player in the metabolic regulation triggered by ribosome impairment. Furthermore, we show that NAC is essential for the survival of the highly oxidative phosphorylation (OXPHOS) reliant intestinal stem cells (ISCs), being translationally regulated itself. NAC interacts with the ribosome and promotes the transport of the translation machinery and newly-formed peptides to the proximity of the mitochondria, allowing the import of proteins essential for processes such as OXPHOS. Upon translation stress, NAC is inhibited through an interaction with ZAKα, leading to the downregulation of OXPHOS. Overall, our findings unveil that NAC is a central player in translation-mediated metabolic regulation in intestinal cells.
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Project description:AATF is a predominantly nuclear protein that has been shown to be an apoptosis-inhibiting factor essential for both embryonic development and tumor growth. Several studies have shown a role of AATF in the modulation of pivotal cellular signal transduction pathways such as p53-, mTOR- and HIF-signaling. However, the exact molecular functions underlying its essential nature to cell proliferation and survival have remained elusive. Interestingly, several lines of evidence point towards a pivotal role of this protein in ribosome biogenesis and the maturation of ribosomal RNA. The function of AATF in this process is not clear, especially since the identity of the RNA-binding protein that links the AATF-containing protein complex (ANN) to rRNA precursors is unknown. In this study, we identify AATF in a screen for RNA-binding proteins. Importantly, AATF does not only bind to polyA-tailed RNA but CLIP-experiments reveal its association with ribosomal RNA. The RNA-binding domain of AATF is essential to maintain its positive effect on cellular rRNA levels. Furthermore, AATF binds to both mRNAs encoding for ribosome biogenesis factors as well as proteins involved with this process indicating AATF to be a central hub for the coordination of ribosome maturation. Consequently, our data for the first time identify the molecular basis to the role of AATF in ribosome biosynthesis and corroborate the link between tumorigenesis and ribosome biology.
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Project description:The RNA-Seq reveal flight-induced ribosome impairment in the cerebellum of racing pigeons
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Project description:Local mRNA translation in axons is critical for the spatial and temporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons, however how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER – ribosome interactions causes defects in axon morphology. Our results establish an important role for the axonal ER in dynamically localizing mRNA translation which is important for proper neuron development.
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