Iron regulation through the back door: iron-dependent metabolite levels contribute to transcriptional adaptation to iron deprivation in Saccharomyces cerevisiae.
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ABSTRACT:
SUBMITTER: Ihrig J
PROVIDER: S-EPMC2837980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The budding yeast Saccharomyces cerevisiae responds to depletion of iron in the environment by activating Aft1p, the major iron-dependent transcription factor, and by transcribing systems involved in the uptake of iron. Here, we have studied the transcriptional response to iron deprivation and have identified new Aft1p target genes. We find that other metabolic pathways are regulated by iron: biotin uptake and biosynthesis, nitrogen assimilation, and purine biosynthesis. Two enzymes active in these pathways, biotin synthase and glutamate synthase, require an iron-sulfur cluster for activity. Iron deprivation activates transcription of the biotin importer and simultaneously represses transcription of the entire biotin biosynthetic pathway. Multiple genes involved in nitrogen assimilation and amino acid metabolism are induced by iron deprivation, whereas glutamate synthase, a key enzyme in nitrogen assimilation, is repressed. A CGG palindrome within the promoter of glutamate synthase confers iron-regulated expression, suggesting control by a transcription factor of the binuclear zinc cluster family. We provide evidence that yeast subjected to iron deprivation undergo a transcriptional remodeling, resulting in a shift from iron-dependent to parallel, but iron-independent, metabolic pathways.
| S-EPMC363115 | biostudies-literature
Project description:BackgroundSaccharomyces cerevisiae is a well-known popular model system for basic biological studies and serves as a host organism for the heterologous production of commercially interesting small molecules and proteins. The central metabolism is at the core to provide building blocks and energy to support growth and survival in normal situations as well as during exogenous stresses and forced heterologous protein production. Here, we present a comprehensive study of intracellular central metabolite pool profiling when growing S. cerevisiae on different carbon sources in batch cultivations and at different growth rates in nutrient-limited glucose chemostats. The latest versions of absolute quantitative mass spectrometry-based metabolite profiling methodology were applied to cover glycolytic and pentose phosphate pathway metabolites, tricarboxylic acid cycle (TCA), complete amino acid, and deoxy-/nucleoside phosphate pools.ResultsGlutamate, glutamine, alanine, and citrate were the four most abundant metabolites for most conditions tested. The amino acid is the dominant metabolite class even though a marked relative reduction compared to the other metabolite classes was observed for nitrogen and phosphate limited chemostats. Interestingly, glycolytic and pentose phosphate pathway (PPP) metabolites display the largest variation among the cultivation conditions while the nucleoside phosphate pools are more stable and vary within a closer concentration window. The overall trends for glucose and nitrogen-limited chemostats were increased metabolite pools with the increasing growth rate. Next, comparing the chosen chemostat reference growth rate (0.12 h-1, approximate one-fourth of maximal unlimited growth rate) illuminates an interesting pattern: almost all pools are lower in nitrogen and phosphate limited conditions compared to glucose limitation, except for the TCA metabolites citrate, isocitrate and α-ketoglutarate.ConclusionsThis study provides new knowledge-how the central metabolism is adapting to various cultivations conditions and growth rates which is essential for expanding our understanding of cellular metabolism and the development of improved phenotypes in metabolic engineering.
| S-EPMC7941957 | biostudies-literature
Project description:Metabolite concentrations can regulate gene expression, which can in turn regulate metabolic activity. The extent to which functionally related transcripts and metabolites show similar patterns of concentration changes, however, remains unestablished. We have therefore measured and analyzed the metabolomic (previously published in Brauer et al., PMID 17159141) and transcriptional responses (presented here) of Saccharomyces cerevisiae to carbon and nitrogen starvation.
2009-02-02 | GSE11754 | GEO
Project description:Furfural, one of the most common inhibitors in pre-treatment hydrolysates, reduces the cell growth and ethanol production of yeast. Evolutionary engineering has been used as a selection scheme to obtain yeast strains that exhibit furfural tolerance. However, the response of Saccharomyces cerevisiae to furfural at the metabolite level during evolution remains unknown. In this study, evolutionary engineering and metabolomic analyses were applied to determine the effects of furfural on yeasts and their metabolic response to continuous exposure to furfural. After 50 serial transfers of cultures in the presence of furfural, the evolved strains acquired the ability to stably manage its physiological status under the furfural stress. A total of 98 metabolites were identified, and their abundance profiles implied that yeast metabolism was globally regulated. Under the furfural stress, stress-protective molecules and cofactor-related mechanisms were mainly induced in the parental strain. However, during evolution under the furfural stress, S. cerevisiae underwent global metabolic allocations to quickly overcome the stress, particularly by maintaining higher levels of metabolites related to energy generation, cofactor regeneration and recovery from cellular damage. Mapping the mechanisms of furfural tolerance conferred by evolutionary engineering in the present study will be led to rational design of metabolically engineered yeasts.
| S-EPMC5328829 | biostudies-literature
Project description:Mating-type switching in the budding yeast Saccharomyces cerevisiae relies on the Sir protein complex to silence HML and HMR, the two loci containing copies of the alleles of the mating type locus, MAT. Sir-based transcriptional silencing has been considered locus-specific, but the recent discovery of rare and transient escapes from silencing at HMLα2 with a sensitive assay called to question if these events extend to the whole locus. Adapting the same assay, we measured that transient silencing failures at HML were more frequent for the α2 gene than α1, similarly to their expression level in unsilenced cells. By coupling a mating assay, at HML we found that one of the two genes at that locus can be transiently expressed while the other gene is maintained silent. Thus, transient silencing loss can be a property of the gene rather than the locus. Cells lacking the SIR1 gene experience epigenetic bistability at HML and HMR. Our previous result led us to ask if HML could allow for two independent epigenetic states within the locus in a sir1Δ mutant. A simple construct using a double fluorescent reporter at HMLα1 and HMLα2 ruled out this possibility. Each HML locus displayed a single epigenetic state. We revisited the question of the correlation between the states of two HML loci in diploid cells, and showed they were independent. Finally, we determined the relative strength of gene repression achieved by Sir-based silencing with that achieved by the a1-α2 repressor.
| S-EPMC9910407 | biostudies-literature
Project description:Iron is an essential cofactor for enzymes involved in numerous cellular processes, yet little is known about the impact of iron deficiency on cellular metabolism or iron proteins. Previous studies have focused on changes in transcript and proteins levels in iron-deficient cells, yet these changes may not reflect changes in transport activity or flux through a metabolic pathway. We analyzed the metabolomes and transcriptomes of yeast grown in iron-rich and iron-poor media to determine which biosynthetic processes are altered when iron availability falls. Iron deficiency led to changes in glucose metabolism, amino acid biosynthesis, and lipid biosynthesis that were due to deficiencies in specific iron-dependent enzymes. Iron-sulfur proteins exhibited loss of iron cofactors, yet amino acid synthesis was maintained. Ergosterol and sphingolipid biosynthetic pathways had blocks at points where heme and diiron enzymes function, whereas Ole1, the essential fatty acid desaturase, was resistant to iron depletion. Iron-deficient cells exhibited depletion of most iron enzyme activities, but loss of activity during iron deficiency did not consistently disrupt metabolism. Amino acid homeostasis was robust, but iron deficiency impaired lipid synthesis, altering the properties and functions of cellular membranes.
| S-EPMC2863190 | biostudies-literature
Project description:Ethanol is the main by-product of yeast sugar fermentation that affects microbial growth parameters, being considered a dual molecule, a nutrient and a stressor. Previous works demonstrated that the budding yeast arose after an ancient hybridization process resulted in a tier of duplicated genes within its genome, many of them with implications in this ethanol "produce-accumulate-consume" strategy. The evolutionary link between ethanol production, consumption, and tolerance versus ploidy and stability of the hybrids is an ongoing debatable issue. The implication of ancestral duplicates in this metabolic rewiring, and how these duplicates differ transcriptionally, remains unsolved. Here, we study the transcriptomic adaptive signatures to ethanol as a nonfermentative carbon source to sustain clonal yeast growth by experimental evolution, emphasizing the role of duplicated genes in the adaptive process. As expected, ethanol was able to sustain growth but at a lower rate than glucose. Our results demonstrate that in asexual populations a complete transcriptomic rewiring was produced, strikingly by downregulation of duplicated genes, mainly whole-genome duplicates, whereas small-scale duplicates exhibited significant transcriptional divergence between copies. Overall, this study contributes to the understanding of evolution after gene duplication, linking transcriptional divergence with duplicates' fate in a multigene trait as ethanol tolerance.IMPORTANCE Gene duplication events have been related with increasing biological complexity through the tree of life, but also with illnesses, including cancer. Early evolutionary theories indicated that duplicated genes could explore alternative functions due to relaxation of selective constraints in one of the copies, as the other remains as ancestral-function backup. In unicellular eukaryotes like yeasts, it has been demonstrated that the fate and persistence of duplicates depend on duplication mechanism (whole-genome or small-scale events), shaping their actual genomes. Although it has been shown that small-scale duplicates tend to innovate and whole-genome duplicates specialize in ancestral functions, the implication of duplicates' transcriptional plasticity and transcriptional divergence on environmental and metabolic responses remains largely obscure. Here, by experimental adaptive evolution, we show that Saccharomyces cerevisiae is able to respond to metabolic stress (ethanol as nonfermentative carbon source) due to the persistence of duplicated genes. These duplicates respond by transcriptional rewiring, depending on their transcriptional background. Our results shed light on the mechanisms that determine the role of duplicates, and on their evolvability.
| S-EPMC7426151 | biostudies-literature
Project description:The propagation of information through signaling cascades spans a wide range of time scales, including the rapid ligand-receptor interaction and the much slower response of downstream gene expression. To determine which dynamic range dominates a response, we used periodic stimuli to measure the frequency dependence of signal transduction in the osmo-adaptation pathway of Saccharomyces cerevisiae. We applied system identification methods to infer a concise predictive model. We found that the dynamics of the osmo-adaptation response are dominated by a fast-acting negative feedback through the kinase Hog1 that does not require protein synthesis. After large osmotic shocks, an additional, much slower, negative feedback through gene expression allows cells to respond faster to future stimuli.
| S-EPMC2916730 | biostudies-literature
Project description:BACKGROUND: Propolis is a natural product of plant resins collected by honeybees (Apis mellifera) from various plant sources. Our previous studies indicated that propolis sensitivity is dependent on the mitochondrial function and that vacuolar acidification and autophagy are important for yeast cell death caused by propolis. Here, we extended our understanding of propolis-mediated cell death in the yeast Saccharomyces cerevisiae by applying systems biology tools to analyze the transcriptional profiling of cells exposed to propolis. METHODS: We have used transcriptional profiling of S. cerevisiae exposed to propolis. We validated our findings by using real-time PCR of selected genes. Systems biology tools (physical protein-protein interaction [PPPI] network) were applied to analyse the propolis-induced transcriptional bevavior, aiming to identify which pathways are modulated by propolis in S. cerevisiae and potentially influencing cell death. RESULTS: We were able to observe 1,339 genes modulated in at least one time point when compared to the reference time (propolis untreated samples) (t-test, p-value 0.01). Enrichment analysis performed by Gene Ontology (GO) Term finder tool showed enrichment for several biological categories among the genes up-regulated in the microarray hybridization such as transport and transmembrane transport and response to stress. Real-time RT-PCR analysis of selected genes showed by our microarray hybridization approach was capable of providing information about S. cerevisiae gene expression modulation with a considerably high level of confidence. Finally, a physical protein-protein (PPPI) network design and global topological analysis stressed the importance of these pathways in response of S. cerevisiae to propolis and were correlated with the transcriptional data obtained thorough the microarray analysis. CONCLUSIONS: In summary, our data indicate that propolis is largely affecting several pathways in the eukaryotic cell. However, the most prominent pathways are related to oxidative stress, mitochondrial electron transport chain, vacuolar acidification, regulation of macroautophagy associated with protein target to vacuole, cellular response to starvation, and negative regulation of transcription from RNA polymerase II promoter. Our work emphasizes again the importance of S. cerevisiae as a model system to understand at molecular level the mechanism whereby propolis causes cell death in this organism at the concentration herein tested. Our study is the first one that investigates systematically by using functional genomics how propolis influences and modulates the mRNA abundance of an organism and may stimulate further work on the propolis-mediated cell death mechanisms in fungi.
| S-EPMC3598864 | biostudies-literature
Project description:BackgroundIon homeostasis is essential for every cell and aberrant cation homeostasis is related to diseases like Alzheimer's disease and epilepsy. The mechanisms responsible for cation homeostasis are only partly understood. The yeast Saccharomyces cerevisiae is an excellent organism to study fundamental aspects of cation homeostasis. In this study we investigated the transcriptional response of this yeast to potassium starvation by using Serial Analysis of Gene Expression (SAGE)-tag sequencing.ResultsComparison of transcript levels in cells grown for 60 min in media without potassium with those in cells grown under standard potassium concentrations showed that the mRNA levels of 105 genes were significantly (P < 0.01) up-regulated more than 2.0-fold during potassium starvation and the mRNA levels of 172 genes significantly down-regulated. These genes belong to several functional categories. Genes involved in stress response including HSP30, YRO2 and TPO2 and phosphate metabolism including PHO84, PHO5 and SPL2 were highly up-regulated. Analysis of the promoter of PHO84 encoding a high affinity phosphate transporter, revealed that increased PHO84 RNA levels are caused by both increased Pho4-dependent transcription and decreased RNA turnover. In the latter process antisense transcription may be involved. Many genes involved in cell cycle control, and to a lesser extent genes involved in amino acid transport, were strongly down-regulated.ConclusionsOur study showed that yeast cells respond to potassium starvation in a complex way and reveals a direct link between potassium homeostasis and phosphate metabolism.
| S-EPMC4289377 | biostudies-literature