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MTOR-dependent translation amplifies microglia priming in ageing

ABSTRACT: mTOR-dependent translation amplifies microglia priming in ageing

PROVIDER: PRJNA658992 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12508040_1.fastq.gz	Fastqsanger.gz
	SRR12508040_2.fastq.gz	Fastqsanger.gz
	SRR12508041_1.fastq.gz	Fastqsanger.gz
	SRR12508041_2.fastq.gz	Fastqsanger.gz
	SRR12508042_1.fastq.gz	Fastqsanger.gz

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mTOR-dependent translation amplifies microglia priming in ageing

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

mTOR-dependent translation amplifies microglia priming in aging mice.

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 had upregulated mTOR complex 1 signaling controlling translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual yet contrasting effect on microglia priming: it caused an NF-κB-dependent upregulation of priming genes at the 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, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration.

| S-EPMC7773382 | biostudies-literature

nanoCAGE reveals 5â UTR features that define specific modes of translation of functionally related mTOR-sensitive mRNAs

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

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [4C]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [4C]

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Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [RELACS]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [RELACS]

| PRJNA1267103 | ENA

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [Multiome]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [Multiome]

| PRJNA1267109 | ENA

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [ATAC-Seq]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [ATAC-Seq]

| PRJNA1267099 | ENA

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [CUT&Run]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [CUT&Run]

| PRJNA1267101 | ENA

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [RNA-Seq]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [RNA-Seq]

| PRJNA1267102 | ENA

Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [Micro-C]

Project description:Stage-specific Epigenetic Priming Amplifies Gene Activation During Lineage Commitment [Micro-C]

| PRJNA1267113 | ENA

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