Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection
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PROVIDER: PRJNA509132 | ENA |
REPOSITORIES: ENA
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Project description:Optimal health requires perpetual transcriptional fidelity of gene expression. SKN-1/NRF2 is a cytoprotective transcription factor in C. elegans that regulates the expression of cellular defenses during stress, including: nutrient deprivation, redox imbalance, and xenobiotic and pathogen exposure. Constitutive activation of SKN-1 results in pleiotropic outcomes, including shortened lifespan and protective redistribution of somatic fat to the germline. We measured lipid distribution between the soma and germ tissues after manipulation of SKN-1 activity. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets and alleviates negative metabolic outcomes. Similarly, paraquat exposure redirects SKN-1 activity toward oxidative stress responses and away from pathogen response genes, which restores lipid distribution across tissues. Lastly, activating p38 MAPK signaling is sufficient to drive SKN-1-dependent loss of somatic fat. These data reveal a coordination of organismal metabolic homeostasis with pathogen responses and identifies mechanisms for counteracting the pleiotropic consequences of aberrant transcriptional activity.
2019-10-15 | GSE123531 | GEO
Project description:Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons in C. elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.
2023-12-06 | GSE246466 | GEO
Project description:Excess iodide could lead to larve arrest to C. elegans, we screened for mutants that can survive in excess iodide and identified gain-of-function mutations in skn-1 and loss-of-function mutations in wdr-23 and bli-3. Genetic study uncover that wdr-23(lf) can interact with bli-3 mutations in a manner different from skn-1(gf). Transcriptome studies suggest that excess iodide causes developmental arrest largely independent of changes in gene expression, and wdr-23(lf) could affect the expression of a subset of genes by a mechanism different from SKN-1 activation.
2018-07-18 | GSE117222 | GEO
Project description:Coordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons in C. elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.
2023-12-06 | GSE246465 | GEO
Project description: Not available
| S-EPMC6825279 | biostudies-literature
Project description:Aging is a major international concern and brings with it formidable socioeconomical and healthcare challenges. An attainable approach to improve general health in humans is using small molecules. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits aging-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in the aging animal model C. elegans, which shares many major longevity pathways with those of mammals. Tomatidine improves behaviors related to healthspan, including increased pharyngeal pumping and swimming movement, and also reduces deterioration of muscle cells in worms. Microarray, imaging, and behavioral analysis reveal that tomatidine maintains mitochondrial homeostasis through mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the cellular antioxidant response SKN-1/Nrf2 pathway, followed by increased mitophagy in worms, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions towards diseases of aging.
2017-08-21 | GSE85237 | GEO
Project description:Analysis of gastrocnemius from male wild type(WT) and Skn-1-deficient mice. Skn-1-deficient mice have reduced body weight with low body fat due to increased energy expenditure. Results provide insight into the molecular mechanisms up-regulating metabolism.
2017-02-11 | GSE76936 | GEO
Project description:WGS and RNA-seq data for Nrf2 study
| EGAS00001001740 | EGA
Project description:The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins TRX-2 and TRX-3 do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, SKN-1 transcriptional activity remains largely unaffected. Interestingly, RNA-Seq revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport and localization being most prevalent. However, one prominent lipase-related gene, lips-6, is highly up regulated upon loss of trx-1 in a skn-1-dependent manner. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. Four samples were analyzed: Two nematode strains were analyzed, each under non-stressed and stressed (10mM NaAs) conditions
2016-04-01 | E-GEOD-77976 | biostudies-arrayexpress
Project description:The difference in translation between CGCM and SKN-1b mutant
2020-08-13 | E-MTAB-8253 | biostudies-arrayexpress