Insulin-like Signaling Determines Survival During Stress via Post Transcriptional Mechanisms in C. elegans.
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE22383 | GEO | 2010/06/17
SECONDARY ACCESSION(S): PRJNA127629
REPOSITORIES: GEO
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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
Project description:Low complexity “prion-like” domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components including stress granule proteins become highly insoluble with age in C. elegans and that reduced insulin/IGF-1 daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress granule-related RBP aggregates are associated with reduced fitness. We show that HSF-1 is a main regulator of stress granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress granule-related RBPs partly by reducing the build-up of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases.
2017-01-16 | PXD003451 | Pride
Project description:Animals change developmental fates in response to external cues. In the nematode Caenorhabditis elegans, unfavorable environmental conditions induce a state of diapause known as dauer by inhibiting the conserved DAF-2 insulin-like signaling (ILS) pathway through incompletely understood mechanisms. We previously established a role for the C. elegans dosage compensation protein DPY-21 in the control of dauer arrest and DAF-2 ILS. Here we show that dosage compensation acts through the histone H4 lysine 20 methyltransferase SET-4 to promote dauer arrest in part by repressing the X-linked ins-9 gene, which encodes a new agonist insulin-like peptide (ILP) expressed specifically in the paired ASI sensory neurons that are required for dauer bypass. ins-9 repression in dauer-constitutive mutants requires DPY-21, SET-4, and the FoxO transcription factor DAF-16, which is the main target of DAF-2 ILS. In contrast, autosomal genes encoding major agonist ILPs that promote reproductive development are not repressed by DPY-21, SET-4, or DAF-16/FoxO. Our results implicate the dosage compensation machinery as a sensory rheostat that reinforces developmental fates in response to environmental cues by modulating autocrine and paracrine DAF-2 ILS.
2017-02-28 | GSE89295 | GEO
Project description:FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals. Whole-transcriptome profiling of daf-16/FoxO isoform-specific deletion mutants in the long-lived daf-2(e1370) background. Included are daf-16 wild-type, daf-16 null mutation, daf-16a/f mutation, two independent daf-16a mutations, and daf-16f mutation. N2 wild-type controls are also included.
2015-08-27 | E-GEOD-72426 | biostudies-arrayexpress
Project description:FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals.
2015-08-27 | GSE72426 | GEO
Project description:A hallmark of aging is immunosenescence, a decline in immune function that appeared to be inevitable. Surprisingly, here we show that genetic inhibition of DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and even rejuvenates immunity in C. elegans. We find that p38 mitogen activated protein kinase (PMK-1), a key determinant of immunosenescence in wild-type, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of zip-10/bZip transcription factor, which in turn down-regulates ins-7, an agonistic insulin-like peptide, for further reduction in insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via up-regulating anti-aging transcription factors that regulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to developing strategies for immune rejuvenation in humans.
2021-02-26 | GSE137861 | GEO
Project description:A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, includingCaenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age inC. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in olddaf-2(−)animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of thezip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.
2023-10-04 | GSE244494 | GEO
Project description:Investigation of whole genome gene expression level changes in C. elegans rsks-1, daf-2, daf-2 rsks-1 and daf-16; daf-2 rsks-1 mutant compared to the wild-type N2 strain. The mutants have altered longevity phenotypes. The mutants analyzed in this study are further described in Di Chen, Patrick Wai-Lun Li, Benjamin A. Goldstein, Waijiao Cai, Emma Lynn Thomas, Fen Chen, Alan E. Hubbard, Simon Melov and Pankaj Kapahi, Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans, Cell Reports (CELL-REPORTS-D-13-00388).
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Project description:Investigation of whole genome gene expression level changes in C. elegans rsks-1, daf-2, daf-2 rsks-1 and daf-16; daf-2 rsks-1 mutant compared to the wild-type N2 strain. The mutants have altered longevity phenotypes. The mutants analyzed in this study are further described in Di Chen, Patrick Wai-Lun Li, Benjamin A. Goldstein, Waijiao Cai, Emma Lynn Thomas, Fen Chen, Alan E. Hubbard, Simon Melov and Pankaj Kapahi, Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans, Cell Reports (CELL-REPORTS-D-13-00388). A 47 chip study using total RNAs from C. elegans wild-type N2 (9 replicates), rsks-1 mutant (9 replicates), daf-2 mutant (9 replicates), daf-2 rsks-1 double mutant (10 replicates) and daf-16; daf-2 rsks-1 triple mutant (10 replicates) measured gene expression levels at the whole genome level.
2013-11-14 | E-GEOD-52340 | biostudies-arrayexpress
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