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Lifespan extension via eIF4G inhibition is mediated by post-transcriptional remodeling of stress response gene expression in C. elegans

ABSTRACT: Reducing protein synthesis slows growth and development but can increase adult lifespan. We demonstrate that knock-down of eukaryotic translation initiation factor 4G (eIF4G), which is down-regulated during starvation, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for lifespan extension when IFG-1 is inhibited and are new determinants of longevity. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results support a role for IFG-1 in mediating the antagonistic effects on growth and somatic maintenance by modulating translation of a specific class of mRNA based on transcript length.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE28665 | GEO | 2011/04/16

SECONDARY ACCESSION(S): PRJNA138873

REPOSITORIES: GEO

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Lifespan extension via eIF4G inhibition is mediated by post-transcriptional remodeling of stress response gene expression in C. elegans

Project description:Reducing protein synthesis slows growth and development but can increase adult lifespan. We demonstrate that knock-down of eukaryotic translation initiation factor 4G (eIF4G), which is down-regulated during starvation, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for lifespan extension when IFG-1 is inhibited and are new determinants of longevity. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results support a role for IFG-1 in mediating the antagonistic effects on growth and somatic maintenance by modulating translation of a specific class of mRNA based on transcript length. 24 experimental samples were analyzed using custom oligo microarrays. A wild type sample pool was used as the Cy3 reference/control for all experimetal samples. All extracted RNA prior to array analysis was fractioned (via a sucrose gradient) based on ribosomal loading and pooled into ribosomal and free RNA (Fraction1), light polysomes (Fraction2) and heavy polysomes (Fraction3) as described in the experimental procedures. The control RNAi is ‘empty’ vector L4440 RNAi feeding vector plasmid (1999 Firelab vector kit) transformed HT115(DE3), which was obtained from the Caenorhabditis Genetics Center (University of Wisconsin).

2011-04-16 | E-GEOD-28665 | biostudies-arrayexpress

Effects of cadmium and ifg-1 mutant on gene expression and mRNA splicing

Project description:Splicing of pre-mRNA is an essential process for all eukaryotic dividing cells. Pre-mRNA splicing can be influenced by environmental factors and RNA splicing defects are implicated in numerous human diseases. To understand the genetic mechanism of RNA splicing regulation under environmental stress, we performed a genome-wide RNAi screen in C. elegans and identified suppression of protein synthesis leads to strong protection against cadmium-induced RNA splicing defects. Using a mutant with partial loss of function to the C. elegans ifg-1 gene (eIF4G), we performed RNA-sequencing and found that the levels of cadmium-induced alternative splicing observed in the wildtype is highly reduced in the ifg-1 mutant. Transcriptome analysis revealed ifg-1 mutant moderately up-regulate > 80 genes involved in RNA splicing regulation and depletion of core RNA splicing regulators abolish the ifg-1 long-lived phenotype. A secondary RNAi screen revealed depletion of sma-2 and sma-3 suppresses ifg-1’s protection against stress-induced RNA splicing protection, potentially via transcription of ifg-1 up-regulated RNA splicing regulating genes. Lastly, depletion of sma-2 and sma-3 reduces ifg-1’s long-lived phenotype. Our results propose a model where translation suppression via ifg-1 increases RNA splicing fidelity under stress by upregulating RNA splicing regulatory genes via the sma-2/3 pathway that contributes to its longevity phenotype.

2022-05-11 | GSE184491 | GEO

Insulin-like Signaling Determines Survival During Stress via Post Transcriptional Mechanisms in C. elegans.

Project description:The insulin-like signaling (ILS) pathway regulates metabolism and is known to modulate adult lifespan in C. elegans. Altered stress responses and resistance to a wide range of stressors are also associated with changes in ILS and contribute to enhanced longevity. The transcription factors DAF-16 and HSF-1 are key effectors of the longevity phenotype. We demonstrate that increased intrinsic thermotolerance, due to lower ILS, is not dependent on stress induced HSF-1 transcriptional responses but instead requires active protein translation. Translation profiling experiments reveal genes that are post-transcriptionally regulated in response to altered ILS during heat shock in a DAF-16-dependent manner. Furthermore, several novel proteins are specifically required for ILS effects on thermotolerance. We propose that lowered-ILS results in DAF-16-induced metabolic and physiological changes that precondition a translational response to modulated survival under acute stress. 72 experimental samples were analyzed using custom oligo microarrays. A wild type sample pool was used as the Cy3 reference/control for all experimetal samples. All extracted RNA prior to array analysis was fractioned (via a sucrose gradient) based on ribosomal loading and pooled into ribosomal and free RNA (F1), light polysomes (F2) and heavy polysomes (F3) as described in the experimental procedures. The control RNAi is ‘empty’ vector L4440 RNAi feeding vector plasmid (1999 Firelab vector kit) transformed HT115(DE3), which was obtained from the Caenorhabditis Genetics Center (University of Wisconsin).

2010-06-17 | E-GEOD-22383 | biostudies-arrayexpress

A novel oncomicropeptide encoded by DSP-AS1 exhibits proneoplastic properties in lung adenocarcinoma by facilitating YTHDF1-induced translation initiation through mediation of mRNA circularization

Project description:Functional micropeptides can hide inside RNA previously annotated as non-coding, their roles in the tumorigenesis of lung cancer remain largely unknown. Here, combining Ribo-seq, mass spectrometry and bioinformatics, we characterize a 46 amino-acid length oncogenic micropeptide encoded by lncRNA DSP-AS1, that we named Desmoplakin Associated MicroPeptide (DAMP), in lung adenocarcinoma (LUAD). DAMP is aberrantly overexpressed in LUAD and confers an unfavorable prognosis, its pro-neoplastic properties with respect to augmented proliferation, survival and invasiveness were validated in vitro and in vivo. DAMP colocalizes with translation machinery and induces translational reprogramming both by elevating global protein synthesis and by selectively upregulating the translation of mRNA group encoding oncogenic factors in LUAD. Mechanistically, DAMP simultaneously binds cap-binding subunit eIF4G and YTHDF1, a m6A reader that could fuel translation initiation by recruiting eIF3 to methylated mRNA. The above interactions lead to the formation of a “closed loop” between YTHDF1 and eIF4G bridged by DAMP, which makes YTHDF1 to be spatially in proximity with translation initiation complex and successfully loading of ribosomal 40S subunit onto target mRNAs. Targeting DAMP exhibited significant anti-cancer effects in vitro and in vivo. Our findings not only unravel the oncogenic role of a previously unrecognized micropeptide through orchestrating mRNA translation but also provide a strong rationale in the design of anti-cancer therapy targeting translation machinery in LUAD.

2023-12-04 | GSE249133 | GEO

The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs

Project description:Translation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show that eukaryote-specific Asc1/RACK1 is required for efficient translation of mRNAs with short open reading frames that show greater than average translational efficiency in diverse eukaryotes. ASC1 mutants in S. cerevisiae display compromised translation of specific functional groups, including cytoplasmic and mitochondrial ribosomal proteins, and display cellular phenotypes consistent with their gene-specific translation defects. Asc1-sensitive mRNAs are preferentially associated with the translational ‘closed loop’ complex comprised of eIF4E, eIF4G and Pab1, and depletion of eIF4G mimics the translational defects of ASC1 mutants. Together our results reveal a role for Asc1/RACK1 in a length-dependent initiation mechanism optimized for efficient translation of genes with important housekeeping functions.

2016-04-24 | GSE61753 | GEO

TRL-1 undergoes phase separation to regulate the reproduction and longevity tradeoff

Project description:The antagonistic pleiotropy theory of aging proposes that genes enhancing fitness in early life limit lifespan, but the molecular evidence remains underexplored. By profiling translatome changes in Caenorhabditis elegans during starvation recovery, we demonstrate that an open reading frame (ORF) trl-1 'hidden' within an annotated pseudogene significantly translates upon refeeding. trl-1 mutant animals increase brood sizes but shorten lifespan and specifically impair the germline deficiency-induced longevity. The loss of trl-1 abnormally upregulates the translation of vitellogenin that produces copious yolk to provision eggs, whereas vitellogenin overexpression is known to reduce lifespan. We show that TRL-1 protein undergoes liquid-liquid phase separation, through which TRL-1 granules recruit vitellogenin mRNA and inhibit its translation. These results indicate that trl-1 functions as an antagonistic pleiotropic gene to regulate the reproduction-longevity tradeoff by optimizing nutrient production for the next generation.

2022-03-22 | GSE184209 | GEO

Tri-methylation of lysine 36 on H3 restricts gene expression variation during aging and impacts lifespan

Project description:Functional data indicate that specific histone modification enzymes can be key to longevity in Caenorhabditis elegans, but epigenetic mechanisms of lifespan regulation are not well understood. In this study, we profiled the genome-wide pattern of tri-methylation of lysine 36 on histone 3 (H3K36me3) in the somatic cells of young and old C. elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequence on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene-bodies, irrespective of their corresponding mRNA abundance. Importantly, inactivation of the methyltransferase met-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened lifespan, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity. We performed genome-wide mapping of histone H3 and H3K36me3 in young (D2A) and old (D12A) C.elegans somatic cells by ChIP-seq in glp-1(e2141). mRNA-seq was performed in young (D2A) and old (D12A) glp-1(e2141) somatic cells to identify mRNA expression change during aging from D2A to D12A.

2015-04-01 | E-GEOD-62720 | biostudies-arrayexpress

Proteome of C. elegans upon NCL-1 or TIF-IA KD during aging

Project description:Anabolic activities such as ribosome biogenesis and protein synthesis are linked to aging. Ribosomal RNA (rRNA) synthesis is the limiting step of ribosome biogenesis, thus dictating the number of ribosomes in cells and, consequently, the capacity for mRNA translation. Knockdown of the rRNA synthesis repressor, NCL-1, accelerated aging, whereas knocking down the transcription initiation factor C36E8.1 promoted longevity. This suggested that rRNA synthesis has a negative correlation with lifespan. To investigate the metabolic changes upon manipulation of rRNA synthesis the proteome of NCL-1 KD and C36E8.1 KD were analyzed at young, middle, and old age (AD2, AD6, AD12).

2024-01-11 | PXD028600 | Pride

Tri-methylation of lysine 36 on H3 restricts gene expression variation during aging and impacts lifespan

2015-04-01 | GSE62720 | GEO

RNA-seq data for: A conserved mito-cytoplasmic translational balance links two longevity pathways

Project description:Slowing down mRNA translation in either the cytoplasm or the mitochondria are both conserved longevity mechanisms. Here, we found a non-interventional natural correlation of mitochondrial and cytoplasmic ribosomal proteins when looking at mouse population genetics, suggesting a mito-cytoplasmic translational balance. Additionally, inhibiting mitochondrial translation in C. elegans in turn reduced cytoplasmic translation and repressed growth pathways while upregulating stress responses at both proteome and transcriptome levels. This coordinated repression of cytoplasmic translation is dependent on the atf-5/Atf4 transcription factor and is conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with the antibiotic doxycycline. Lastly, extending this to a mammalian setting using doxycycline-treated germ-free mice, we found repressed cytoplasmic translation and ribosomal proteins in liver. These data demonstrate that inhibiting mitochondrial translation initiates a signaling cascade leading to coordinated repression of cytoplasmic translation, unlike previously described unidirectional cyto-to-mito translational communication in yeast, which can be targeted to promote healthy aging.

2019-12-11 | GSE122097 | GEO

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