Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway

Gonzales, Kevin Edmond; Kayıkçı, Ömür; Schaeffer, David G.; Magwene, Paul M.

doi:10.1186/1752-0509-7-40

Cited by 14 publications

(22 citation statements)

References 59 publications

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“…A study investigating the short-term behaviour of cAMP signalling revealed that the cAMP concentration rapidly increases following glucose stimulation. After reaching a peak, the concentration of cAMP then declines to a new steady state that is higher than its initial concentration [ 66 , 67 ]. Based on previous reports and our observations, we suggest that glucose-sensing systems become lethargic during the GX stage.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the transcription factors Thi2p and Nrm1p alleviates the post-glucose effect on xylose utilization in Saccharomyces cerevisiae

Shan

Liu

et al. 2018

Biotechnol Biofuels

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BackgroundThe recombinant Saccharomyces cerevisiae strains that acquired the ability to utilize xylose through metabolic and evolutionary engineering exhibit good performance when xylose is the sole carbon source in the medium (designated the X stage in the present work). However, the xylose consumption rate of strains is generally low after glucose depletion during glucose–xylose co-fermentation, despite the presence of xylose in the medium (designated the GX stage in the present work). Glucose fermentation appears to reduce the capacity of these strains to “recognize” xylose during the GX stage, a phenomenon termed the post-glucose effect on xylose metabolism.ResultsTwo independent xylose-fermenting S. cerevisiae strains derived from a haploid laboratory strain and a diploid industrial strain were used in the present study. Their common characteristics were investigated to reveal the mechanism underlying the post-glucose effect and to develop methods to alleviate this effect. Both strains showed lower growth and specific xylose consumption rates during the GX stage than during the X stage. Glycolysis, the pentose phosphate pathway, and translation-related gene expression were reduced; meanwhile, genes in the tricarboxylic acid cycle and glyoxylic acid cycle demonstrated higher expression during the GX stage than during the X stage. The effects of 11 transcription factors (TFs) whose expression levels significantly differed between the GX and X stages in both strains were investigated. Knockout of THI2 promoted ribosome synthesis, and the growth rate, specific xylose utilization rate, and specific ethanol production rate of the strain increased by 17.4, 26.8, and 32.4%, respectively, in the GX stage. Overexpression of the ribosome-related genes RPL9A, RPL7B, and RPL7A also enhanced xylose utilization in a corresponding manner. Furthermore, the overexpression of NRM1, which is related to the cell cycle, increased the growth rate by 8.7%, the xylose utilization rate by 30.0%, and the ethanol production rate by 76.6%.ConclusionsThe TFs Thi2p and Nrm1p exerted unexpected effects on the post-glucose effect, enhancing ribosome synthesis and altering the cell cycle, respectively. The results of this study will aid in maintaining highly efficient xylose metabolism during glucose–xylose co-fermentation, which is utilized for lignocellulosic bioethanol production.Electronic supplementary materialThe online version of this article (10.1186/s13068-018-1112-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Disruption of the transcription factors Thi2p and Nrm1p alleviates the post-glucose effect on xylose utilization in Saccharomyces cerevisiae

Shan

Liu

et al. 2018

Biotechnol Biofuels

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“…The fitness transgressivity of pde2Δ / Δ cells in periodic salt stress suggests that the positive selection of such mutations may be even stronger if environmental conditions fluctuate. In addition, the output of the cAMP/PKA pathway is likely governed by its dynamic properties, since intracellular levels of cAMP oscillate (Gonzales et al , ), with consequences on nucleo‐cytoplasmic oscillations of Msn2p (Garmendia‐Torres et al , ). The activity of Pde2p is itself modulated by PKA (Hu et al , , 2), and this negative feedback is probably important for suitable dynamics (Gonzales et al , ).…”

Section: Discussionmentioning

confidence: 99%

Genomics of cellular proliferation in periodic environmental fluctuations

Salignon

Richard

Fulcrand

et al. 2018

Molecular Systems Biology

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Living systems control cell growth dynamically by processing information from their environment. Although responses to a single environmental change have been intensively studied, little is known about how cells react to fluctuating conditions. Here, we address this question at the genomic scale by measuring the relative proliferation rate (fitness) of 3,568 yeast gene deletion mutants in out‐of‐equilibrium conditions: periodic oscillations between two environmental conditions. In periodic salt stress, fitness and its genetic variance largely depended on the oscillating period. Surprisingly, dozens of mutants displayed pronounced hyperproliferation under short stress periods, revealing unexpected controllers of growth under fast dynamics. We validated the implication of the high‐affinity cAMP phosphodiesterase and of a regulator of protein translocation to mitochondria in this group. Periodic oscillations of extracellular methionine, a factor unrelated to salinity, also altered fitness but to a lesser extent and for different genes. The results illustrate how natural selection acts on mutations in a dynamic environment, highlighting unsuspected genetic vulnerabilities to periodic stress in molecular processes that are conserved across all eukaryotes.

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“…In addition, the output of the cAMP/PKA pathway is most likely governed by its dynamic properties, since intracellular levels of cAMP oscillate, with consequences on the stress response nucleo-cytoplasmic oscillations of Msn2p 53 . The activity of Pde2p is itself modulated by PKA 54 , and this negative feedback is probably important for suitable dynamics 55 . Our results suggest that loss of this feedback confers a hyperproliferative advantage and that it therefore constitutes a genetic vulnerability during prolonged exposure to periodic stress.…”

Section: Discussionmentioning

confidence: 99%

Genomics of cellular proliferation under periodic stress

Salignon

Richard

Fulcrand

et al. 2017

Preprint

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17 18 19 20Living systems control cell growth dynamically by processing information from their 21 environment. Although responses to one environmental change have been intensively studied, 22 their glucose-mediated degradation resulted in a growth delay that was negligible after one 59 galactose-to-glucose change but significant over multiple changes 8 . This effect is due to short-60 term 'memory' of galactose exposures, which is mediated by GAL1 transcripts that are 61 produced during the galactose condition and later compete for translation with transcripts of 62 the CLN3 cyclin during the glucose condition. Other memorization effects were observed on 63 bacteria during repeated lactose to glucose transitions, this time due to both short-term 64 memory conferred by persistent gene expression and long-term memory conferred by protein 65 stability 9 . 66 67The yeast response to high concentrations of salt is one of the best studied mechanism 68 of cellular adaptation. When extracellular salinity increases abruptly, cell-size immediately 69 reduces and yeast triggers a large process of adaptation. The translation program 10,11 and 70 turnover of mRNAs 12 are re-defined, calcium accumulates in the cytosol and activates the 71 calcineurin pathway 13 , osmolarity sensors activate the High Osmolarity Glycerol MAPK 72 pathway 13,14 , glycerol accumulates intracellularly as a harmless compensatory solute 14 , and 73 membrane transporters extrude excessive ions 13 . Via this widespread adaptation, hundreds of 74 genes are known to participate to growth control after a transition to high salt. What happens 75 in the case of multiple osmolarity changes is less clear, but can be investigated by periodic 76 stimulations of the adaptive response. For example, periodic transitions between 0 and 0.4M 77 NaCl showed that MAPK activation was efficient and transient after each stress except in the 78 range of ~8 min periods, where sustained activation of the response severely hampered cell 79 growth 15 . How genes involved in salt tolerance contribute to cell growth in specific dynamic 80 regimes is unknown. If a protein participates to the late phase of adaptation its mutation may 81 have a strong impact at large periods and no impact at short ones. It is also possible that 82 mutations affecting growth in dynamic conditions have been missed by long-term adaptation 83

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Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway

Cited by 14 publications

References 59 publications

Disruption of the transcription factors Thi2p and Nrm1p alleviates the post-glucose effect on xylose utilization in Saccharomyces cerevisiae

Disruption of the transcription factors Thi2p and Nrm1p alleviates the post-glucose effect on xylose utilization in Saccharomyces cerevisiae

Genomics of cellular proliferation in periodic environmental fluctuations

Genomics of cellular proliferation under periodic stress

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