Transcriptional redirection of activated SKN-1/NRF2 abates the negative metabolic outcomes of a perceived pathogen infection
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ABSTRACT:
PROVIDER: PRJNA509132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8309210_1.fastq.gz | Fastqsanger.gz | |||
| SRR8309210_2.fastq.gz | Fastqsanger.gz | |||
| SRR8309220_1.fastq.gz | Fastqsanger.gz | |||
| SRR8309220_2.fastq.gz | Fastqsanger.gz | |||
| SRR8309211_1.fastq.gz | Fastqsanger.gz |
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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:When an organism encounters a pathogen, the host innate immune system is activated to defend against pathogen colonization and the toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa (PA14) including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy to PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave while continuing to feed on the pathogen even when a non-pathogenic food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display a typical intestinal distension from PA14 colonization and eventual demise, but surprisingly, fail to learn to avoid pathogen with training. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling from both neurons and non-neuronal tissues that drives the pathogen apathy behavior and pleiotropic responses to selective serotonin reuptake inhibitors (SSRIs). Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.
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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.
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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.
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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.
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Project description:Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.
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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.
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Project description:In the presence of stressful environments, the SKN-1 cytoprotective transcription factor is activated to induce the expression of gene targets that can restore homeostasis. However, constitutive activation of SKN-1 results in diminished health and a reduction of lifespan. Here we demonstrate the necessity to regulate the activity of SKN-1 for maintaining the longevity promoting responses associated with impaired daf-2/insulin receptor signaling, the eat-2 model of caloric restriction, and glp-1-dependent loss of germ cell proliferation. A hallmark of animals with constitutive SKN-1 activation is the age-dependent loss of somatic lipids and this phenotype is linked to the general reduction in survival in animals harboring the skn-1gf allele, but surprisingly, daf-2lf; skn-1gf double mutant animals do not redistribute somatic lipids which suggests the insulin signaling pathway functions downstream of SKN-1 in the maintenance of lipid distribution. As expected, eat-2lf; skn-1gf double mutant animals, which independently activate SKN-1, continue to display somatic lipid depletion in older ages with and without the skn-1gf activating mutation but animals lacking a proliferating germline do not redistribute somatic lipids, which supports a genetic model where SKN-1 activity is an important regulator of lipid mobilization in response to food availability to fuel the developing germline by engaging the daf-2/insulin receptor pathway.
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