Hsp90 Stress Potentiates Rapid Cellular Adaptation through Induction of Aneuploidy
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE34087 | GEO | 2011/12/31
SECONDARY ACCESSION(S): PRJNA149981
REPOSITORIES: GEO
Similar Datasets
Project description:Aneuploidy--the state of having uneven numbers of chromosomes--is a hallmark of cancer and a feature identified in yeast from diverse habitats. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could induce aneuploidy in budding yeast (Saccharomyces cerevisae). We show that whereas diverse stress conditions can induce an increase in chromosome instability, proteotoxic stress, caused by transient Hsp90 (also known as Hsp82 or Hsc82) inhibition or heat shock, markedly increased chromosome instability to produce a cell population with high karyotype diversity. The induced chromosome instability is linked to an evolutionarily conserved role for the Hsp90 chaperone complex in kinetochore assembly. Continued growth in the presence of an Hsp90 inhibitor resulted in the emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress potentiated fast adaptation to unrelated cytotoxic compounds by means of different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fuelling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress.
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Project description:This SuperSeries is composed of the following subset Series: GSE34085: Karyotype analysis of radicicol-resistant yeast colonies by array CGH (Radr1,2,3) GSE34086: Genome structure of radicicol-induced aneuploids in yeast by array CGH Refer to individual Series
2011-12-31 | E-GEOD-34087 | biostudies-arrayexpress
Project description:Aneuploid yeast cells are in a chronic state of proteotoxicity, yet do not constitutively induce the cytosolic unfolded protein response, or heat shock response (HSR) by heat shock factor 1 (Hsf1). Here, we demonstrate that an active environmental stress response (ESR), a hallmark of aneuploidy across different models, suppresses Hsf1 induction in models of single-chromosome gain. Furthermore, engineered activation of the ESR in the absence of stress was sufficient to suppress Hsf1 activation in euploid cells by subsequent heat shock while increasing thermotolerance and blocking formation of heat-induced protein aggregates. Suppression of the ESR in aneuploid cells resulted in longer cell doubling times and decreased viability in the presence of additional proteotoxicity. Last, we show that in euploids, Hsf1 induction by heat shock is curbed by the ESR. Strikingly, we found a similar relationship between the ESR and the HSR using an inducible model of aneuploidy. Our work explains a long-standing paradox in the field and provides new insights into conserved mechanisms of proteostasis with potential relevance to cancers associated with aneuploidy.
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Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question of whether this unusual somatic genetic variation evolved as an adaptive mechanism in response to hepatic injury. According to this model, hepatotoxic insults select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16. Loss of the remaining Hgd allele protects from fumarylacetoacetate hydrolase (Fah) deficiency, a genetic liver disease model. When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was approximately 50%. This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans remains under investigation.
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Project description:Aneuploidy, which refers to unbalanced chromosome numbers, represents a class of genetic variation that is associated with cancer, birth defects and eukaryotic micro-organisms1-4. Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile4,5, it remains a fundamental question as to whether there are common cellular defects that are associated with aneuploidy. Here we show the existence in budding yeast of a common aneuploidy gene-expression signature that is suggestive of hypo-osmotic stress, using a strategy that enables the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects in aneuploid yeast-cell populations with random and diverse chromosome stoichiometry. Consistently, aneuploid yeast exhibited increased plasma-membrane stress that led to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modelling showed that hypo-osmotic-like stress is a general outcome of the proteome imbalance that is caused by aneuploidy, and also predicted a relationship between ploidy and cell size that was observed in yeast and aneuploid cancer cells. A genome-wide screen uncovered a general dependency of aneuploid cells on a pathway of ubiquitin-mediated endocytic recycling of nutrient transporters. Loss of this pathway, coupled with the endocytic defect inherent to aneuploidy, leads to a marked alteration of intracellular nutrient homeostasis.
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Project description:Candida albicans is a prevalent, opportunistic, human fungal pathogen. Antifungal drug resistance and tolerance are two distinct mechanisms of adaptation to drugs. Studies of mechanisms of drug resistance are limited to the applications of high doses of drugs. Few studies have investigated the effects of subinhibitory amounts of drugs on the development of drug resistance or tolerance. In this study, we found that growth in a subinhibitory amount of fluconazole (FLC), a widely used antifungal drug, for just a short time was sufficient to induce aneuploidy in C. albicans. Surprisingly, the aneuploids displayed fitness loss in the presence of subinhibitory FLC, but a subpopulation of cells could tolerate up to 128 μg/mL FLC. Particular aneuploidy (ChrR trisomy) caused tolerance, not resistance, to FLC. In the absence of FLC, the aneuploids were unstable. Depending on the karyotype, aneuploids might become completely euploid or maintain particular aneuploidy, and, accordingly, the tolerance would be lost or maintained. Mechanistically, subinhibitory FLC was sufficient to induce the expression of several ERG genes and as well as the drug efflux gene MDR1. Aneuploids had a constitutive high-level expression of genes on and outside the aneuploid chromosomes, including most of the ERG genes as well as the drug efflux genes MDR1 and CDR2. Therefore, aneuploids were prepared for FLC challenges. In summary, aneuploidy provides a rapid and reversible strategy of adaptation when C. albicans is challenged with subinhibitory concentrations of FLC. IMPORTANCE Genome instability is a hallmark of C. albicans. Aneuploidy usually causes fitness loss in the absence of stress but confers better fitness under particular stress conditions. Therefore, aneuploidy is considered to be a double-edged sword. Here, we extend the understanding of aneuploidy. We found that aneuploidy arose under weak stress conditions but that it did not confer better fitness to the stress. Instead, it was less fit than its euploid counterparts. If the stress was withdrawn, aneuploidy spontaneously reverted to euploidy. If the stress became stronger, aneuploidy enabled subpopulation growth in a dose-independent manner of the stress. Therefore, we posit that aneuploidy enables the rapid and reversible development of drug tolerance in C. albicans. Further studies are required to investigate whether this is a general mechanism in human fungal pathogens.
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Project description:The physiological role of mesenchymal stem cells (MSCs) is to provide a source of cells to replace mesenchymal-derivatives in stromal tissues with high cell turnover or following stromal tissue damage to elicit repair. Human MSCs have been shown to suppress in vitro T-cell responses via a number of mechanisms including indoleamine 2,3-dioxygenase (IDO). This immunomodulatory capacity is likely to be related to their in vivo function in tissue repair where local, transient suppression of immune responses would benefit differentiation. Further understanding of the impact of locally modulated immune responses by MSCs is hampered by evidence that IDO is not produced or utilized by mouse MSCs. In this study, we demonstrate that IDO-mediated tryptophan starvation triggered by human MSCs inhibits T-cell activation and proliferation through induction of cellular stress. Significantly, we show that despite utilizing different means, immunomodulation of murine T-cells also involves cellular stress and thus is a common strategy of immunoregulation conserved between mouse and humans.
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Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question of whether this unusual somatic genetic variation evolved as an adaptive mechanism in response to hepatic injury. According to this model, hepatotoxic insults select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16. Loss of the remaining Hgd allele protects from fumarylacetoacetate hydrolase (Fah) deficiency, a genetic liver disease model. When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was approximately 50%. This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans remains under investigation.
2012-07-17 | GSE38963 | GEO
Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was ~50%. This result provides proof-of-principle that the selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.
2012-07-16 | E-GEOD-38963 | biostudies-arrayexpress
Project description:Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2?, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.
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