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The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan

ABSTRACT: The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan

PROVIDER: PRJNA338918 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4031070.fastq.gz	Fastqsanger.gz
	SRR4031340.fastq.gz	Fastqsanger.gz
	SRR4031350.fastq.gz	Fastqsanger.gz
	SRR4031360.fastq.gz	Fastqsanger.gz
	SRR4031370.fastq.gz	Fastqsanger.gz

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The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan

Project description:In Saccharomyces cerevisiae, deletion of genes encoding proteins of the large ribosomal subunit (RPLs) increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the mRNA and protein abundance, the ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and to increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations - including ribosomal protein (RP) gene deletions, calorie restriction, rapamycin treatment - and provide an explanation for its role in longevity and stress response. This SuperSeries is composed of the SubSeries listed below.

2017-06-28 | GSE85591 | GEO

The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan [RNA-Seq]

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The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan [ChIP-Seq]

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The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan.

Project description:In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.The transcription factor Gcn4 is known to regulate yeast amino acid synthesis. Here, the authors show that Gcn4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition.

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Multiomics of GCN4-dependent replicative lifespan extension models reveals Gcn4 as a regulator of protein turnover in yeast

Project description:We have shown that multiple tRNA synthetase inhibitors can increase lifespan in both the nematode C. elegans and the budding yeast S. cerevisiae by acting through the conserved transcription factor Gcn4 (yeast) / ATF-4 (worms). To further understand the biology downstream of this conserved transcription factor in the yeast model system, we looked at two different yeast models known to have both upregulated Gcn4, and GCN4-dependent increased replicative lifespan. These two models are rpl31aΔ yeast, and yeast treated with the tRNA synthetase inhibitor borrelidin. We used both proteomic and RNAseq analysis of a block experimental design that included both of these models, to identify GCN4-dependent changes in these two longlived strains of yeast. Proteomic analysis of these yeast indicate that the longlived yeast have increased abundance of proteins involved in amino acid biosynthesis. RNASeq of these same yeast uncovered further regulation of protein turnover, identifying the differential expression of genes associated with both autophagy and with the ubiquitin proteasome system. The data presented here further underscore the important role that GCN4 and its orthologs play in the maintenance of protein homeostasis, which is itself an important hallmark of aging. Importantly, these changes could also have wider-ranging implications in the understanding and treatment of diseases of aging characterized by protein aggregation.

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Gcn4-dependent translation reduction in long-lived ribosomal protein deletion strains

Project description:Deletion of several ribosomal proteins genes (RPKOs) has been shown to extend the lifespan of Saccharomyces cerevisiae in a Gcn4-dependent manner. To characterize the underlying mechanisms, we systematically analyzed the gene expression of both short- and long-lived RPKO strains at multiple levels. We found that up-regulation of amino acid biosynthesis and global down-regulation of protein synthesis are hallmarks of long-lived strains. We provide direct evidence that gene expression changes observed in long-lived strains result from translational up-regulation of GCN4 mRNA via skipping of upstream open reading frames (uORFs), in turn due to slow/defective ribosome assembly. We further demonstrate that Gcn4 acts as a transcriptional repressor on promoters of translation-related genes, thereby globally reducing protein synthesis. Our data suggest that the Gcn4-dependent increase in lifespan can be attributed partially to its ability to dampen the translation capacity of the cell, thereby engaging a well known mechanism of longevity.

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Multiomics of GCN4-dependent replicative lifespan extension models reveals Gcn4 as a regulator of protein turnover in yeast

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VRK-1 Extends Lifespan by Activation of AMPK via Phosphorylation

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