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RNA-seq analysis of germline stem cell removal and loss of SKN-1 in C. elegans

ABSTRACT: In C. elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here we show that a lack of GSCs results in a broad transcriptional reprogramming, in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis, in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease, and suggests that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE63075 | GEO | 2015/07/21

SECONDARY ACCESSION(S): PRJNA266552

REPOSITORIES: GEO

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TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-Autonomously in Caenorhabditis elegans

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

Abalone peptide increases stress resilience and cost-free longevity via SKN-1-governed transcriptional metabolic reprogramming in C. elegans

Project description:A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. We have successfully used loss-or-gain model of stress survival to quantify organismal resilience. As a proof of concept, this is demonstrated in C. elegans exposed to increasing oxidative stress induced by exogenous paraquat and with proteotoxic stress caused by endogenous polyQ and Aβ aggregation, respectively. Based on this, we reveal that abalone peptide AbaPep#07 (SETYELRK) not only promotes survival resilience against paraquat-induced oxidative stress but also confers protection against polyQ- or Aβ-mediated behavioral dysfunction in C. elegans, indicating its capacity against stress and neurodegeneration. Importantly, we further show that the peptide increases physical fitness of aged C. elegans and extends life span without compromise of growth and reproduction, demonstrating its cost-free prolongevity activity. Moreover, we reveal that the peptide induces differential expression of a number of genes, including innate immune, lipid metabolism and metabolic detoxification genes, which are associated with the SKN-1/Nrf transcription factor. Collectively, our findings demonstrate that the novel abalone cryptide AbaPep#07 increases stress survival resilience and cost-free longevity via SKN-1/Nrf-governed transcriptional reprogramming and provide an insight into the neuroprotective and health-promoting potential of cryptides as proteostasis regulators.

2023-11-06 | GSE246759 | GEO

Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection

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

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-Autonomously in Caenorhabditis elegans

2016-04-01 | GSE77976 | GEO

Skn-1-deficient effect on the gastrocnemius

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: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

2023-12-06 | GSE246465 | GEO

XX sex chromosome complement promotes hyperlipidemia and atherosclerosis in mice

Project description:It is well recognized that men and women differ in circulating lipid profiles and consequently coronary artery disease (CAD). While sex hormones like estrogens are thought to protect women from CAD risk by promoting protective lipid profiles, hormone replacement therapy in women paradoxically increases CAD risk. Biological sex is determined by both sex chromosomes and sex hormones. We used mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We found that an XX sex chromosome complement increases food intake, body weight, fat absorption, serum lipid concentrations and atherosclerosis in gonadal male and female mice, indicating a primary effect of sex chromosome complement. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly were increased in XX male and female mice with elevated intestinal lipids. These results reveal that an XX sex chromosome complement promotes the absorption and bioavailability of dietary fat to accelerate the development of atherosclerosis.

2019-04-17 | GSE119497 | GEO

RNA-seq of C. Elegans control vs SKN-1b mutant

Project description:The difference in translation between CGCM and SKN-1b mutant

2020-08-13 | E-MTAB-8253 | biostudies-arrayexpress

Quercetin decreases high-fat diet induced bodyweight gain and accumulation of hepatic and circulating lipids in mice.

Project description:Dietary flavonoids are supposed to be protective against cardiovascular diseases (CVD). Elevated circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. We investigated the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Body weight gain was 29% lower in quercetin-fed mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation reduced hepatic lipid accumulation with 71% (p<0.05). 1H nuclear magnetic resonance serum lipid profiling revealed that the supplementation lowered serum lipids (p<0.0001). Global gene expression profiling of liver showed that key target genes of the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were regulated, in particular Cytochrome P450 2b (Cyp2b) genes. Quercetin can decrease high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels, which might be explained by the regulation of Cytochrome P450 genes under transcriptional control of CAR, an effect which is likely dependent on dietary background. Liver samples were obtained from 24 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a normal-fat diet. During the intervention of 12 weeks, the mice received a high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q). Based on visual inspection, three arrays lacked homogenous hybridization and were therefore excluded.

2014-10-14 | E-GEOD-51343 | biostudies-arrayexpress

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