Nuclear tRNA sequestering slows aging by a mechanism similar to dietary restriction
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
SUBMITTER: James MacDonald
PROVIDER: E-GEOD-37241 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Dietary restriction (DR) is the best-characterized intervention for slowing aging, and reduced signaling through the target of rapamycin (TOR) kinase is believed to be one of the key mechanisms by which DR extends life span in organisms from yeast to mammals. Here we describe a role for nuclear sequestration of tRNA in yeast replicative life span (RLS) extension from DR. DR causes the nuclear tRNA exporter Los1 to become depleted from the nucleus by a mechanism that requires the DNA damage response factor Rad53, and deletion of LOS1 or overexpression of RAD53 is sufficient to extend RLS. We further report that activation of the nitrogen responsive transcription factor Gln3 is the primary mechanism by which DR extends RLS. Gln3 is activated by both branches of the DR response and is required for life span extension. Overexpression of Gln3 extends RLS by approximately 50%.
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Project description:Expression data from four different lifespan-extending conditions: dietary restriction in two different genetic backgrounds (canton-s and a yw, w1118 combination), sir2 overexpression and p53 knockdown (+/-). Comparison of significantly over and under-expressed genes reveals a signature for dietary restriction and lifespan extension. Abstract A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway.
2011-01-20 | GSE26726 | GEO
Project description:Expression data from four different lifespan-extending conditions: dietary restriction in two different genetic backgrounds (canton-s and a yw, w1118 combination), sir2 overexpression and p53 knockdown (+/-). Comparison of significantly over and under-expressed genes reveals a signature for dietary restriction and lifespan extension. Abstract A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway. 42 samples were used in the analysis. Sir2 overexpression flies and the yw, w1118 background DR flies had the same control. Flies were collected at ages 10 and 40 days. Tissue is whole body females.
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Project description:Chemical exposures in fish have been linked to loss of olfaction leading to an inability to detect predators and prey and decreased survival. However, the mechanisms underlying olfactory neurotoxicity are not well characterized, especially in environmental exposures which involve chemical mixtures. We used zebrafish to characterize olfactory transcriptional responses by two model olfactory inhibitors, the pesticide chlorpyrifos (CPF) and mixtures of CPF with the neurotoxic metal copper (Cu). 30 one-year-old adult AB strain zebrafish were exposed, in groups of three, to CPF/Cu concentrations of 0/0, 0.1/0, 0.25/0, 0.6/0, 0/0.1, 0/0.25, 0/0.6, 0.1/0.25, 0.25/0.25, 0.6/0.25.
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Project description:Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory tissues of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose response pattern to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (let-7, miR-7a, miR-128 and miR-138), indicating a role for Cu-mediated toxicity via interference with olfactory neurogenesis. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in olfactory cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) were inversely correlated with the depression of key genes within olfactory signal transduction pathways, which likely contributed to the inhibition of olfactory function. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of fish olfactory system, and identify novel miRNA biomarkers of metal exposures. 12 one-year-old adult AB strain zebrafish were exposed to Cu concentrations of 0, 6.3, 16 and 40 ppb Cu.
2014-04-30 | E-GEOD-46891 | biostudies-arrayexpress
Project description:Mechanisms underlying in utero fetal lung injury remain poorly defined, and a greater understanding of pathways regulating these processes may lead to novel therapies that prevent lung injury before birth. MicroRNAs (miRNAs) are small non-coding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. We sought to determine whether differentially expressed miRNAs in the fetal lung following choriodecidual infection are associated with elevation of amniotic fluid (AF) cytokine levels and acute lung injury in a nonhuman primate model. After inoculating ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) with either Group B Streptococcus (GBS) 1 x 106 colony forming units (n=5) or saline (n=5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled changes in expression. We identified 9 differentially expressed miRNAs (p<0.05, >1.5 fold change) in the GBS-exposed fetal lungs by microarray, but of these only miR-155-5p was significantly elevated by qRT-PCR (p=0.016). The microarray log2 intensity of miR-155-5p positively correlated with fetal lung injury scores and AF IL-1? and TNF-??levels (R2=0.54, p=0.016). In situ hybridization revealed that miR-155-5p is expressed throughout the fetal lung, which led us to investigate mechanisms that regulate miR-155-5p expression. Significantly elevated miR-155-5p expression was observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to IL-6 and TNF-??. Overexpression of miR-155-5p in FeAE cells increased production of IL-6, CCL5/RANTES and CXCL10/IP-10. Using a luciferase reporter assay, we validated FGF9 as an authentic target of miR-155-5p, which is essential to development of the lung mesenchyme and distal epithelial branching. Collectively, these results suggest that a choriodecidual inflammatory response leads to increased AF cytokine levels, which induce miR-155-5p expression. In turn, miR-155-5p activates and recruits leukocytes (IL-6, CCL5/RANTES) and inhibits fetal lung angiogenesis (CXCL10/IP-10), meschenchymal development and epithelial branching (targets FGF9 mRNA). A therapy to antagonize miR-155-5p may ameliorate perinatal lung injury. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.
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2006-03-07 | E-GEOD-4402 | biostudies-arrayexpress
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