Growth control of the eukaryote cell: a systems biology study in yeast

Castrillo, Juan I.; Zeef, Leo; Hoyle, David C.; Zhang, Nianshu; Hayes, Andrew; Gardner, David C.; Cornell, Michael; Petty, June; Hakes, Luke; Wardleworth, Leanne; Rash, Bharat; Brown, Marie; Dunn, Warwick B.; Broadhurst, David; O'Donoghue, Kerry; Hester, Svenja; Dunkley, Tom; Hart, Sarah R.; Swainston, Neil; Li, Peter; Gaskell, Simon J.; Paton, Norman W.; Lilley, Kathryn S.; Kell, Douglas B.; Oliver, Stephen G.

doi:10.1186/jbiol54

Cited by 250 publications

(294 citation statements)

References 119 publications

(128 reference statements)

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“…Perturbations cause very specific and precise adaptations of the cellular enzyme content, indicating that monitoring of the network occurs at multiple nodes [17]. Balancing the perturbation is then manifold; consequences range from fine-tuning of a few enzymes up to adjusting the overall growth rate [17,[20][21][22][23]. The latter is energetically expensive; a change in the growth rate requires numerous metabolic transitions, and the entire transcriptome, proteome and metabolome must be adapted [23].…”

Section: Glossarymentioning

confidence: 99%

“…Changes in the growth rate are crucial for a cell; they entail a fundamental rearrangement of the cellular physiology and are energetically very costly [23]. It is therefore advantageous to be able to predict, in advance, the requirements for such changes.…”

Section: Glossarymentioning

confidence: 99%

“…In yeast, growth stimuli cooperatively upregulate SAM biosynthetic enzymes. Furthermore, it redirects the metabolic flux through the folate synthesis pathway and increases the production of the SAM precursor, 5-methyl-tetrahydropteroyltriglutamate [23]. SAM plays an interesting dual function in the pathogenic bacterium Listeria monocytogenes, where its synthesis is monitored by up to seven classic riboswitches, which sense the SAM concentration and modulate the expression of methionine/ cysteine transporters and metabolic enzymes [49,50].…”

Section: Reviewmentioning

confidence: 99%

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Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.Evolution of the metabolic network and its structure Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid-or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent and counteract perturbations in the flux, many biological control and sensor systems have evolved around the metabolic network. Metabolic pathways provide the cell with energy and supply macromolecular synthesis pathways with their required intermediates. They also balance metabolic systems under a variety of physiological conditions, and act as transducers and sensor systems for environmental conditions and stimuli. In addition, metabolic pathways are essential for crosstalk between metabolic regulatory components and the cellular transcriptome and proteome.As early as the 1960s, the principle that cells alter their gene expression in response to metabolic requirements has been known. The seminal work of Jacob and Monod, investigating the lac operon, uncovered one of the first examples of chemical-genetic regulation, by which bacterial cells adjust their enzyme production to the nutrient supply [3]. However, only recently have the broader implications of this principle emerged. Indeed, changes in the metabolic network not only control the metabolome, but they also have wide-ranging regulatory functions throughout biology.Most of the biochemical mechanisms that link the metabolic network to the transcriptome and proteome are incompletely understood. However, one type of regulation appears to be common: representative network intermediates bind to and modulate sensor function and activity of transcription factors, translational regulators, chromatin, enzymes, RNA molecules, and ion channels. Significant transcriptional changes around these intermediates identified them as reporter metabolites [4,5]. The use of intermediates as activity reporters ne...

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Section: Glossarymentioning

confidence: 99%

Section: Glossarymentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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“…However, because deletion of SFP1 generates a slow-growing phenotype, which is particularly evident on fermentable carbon sources (Cipollina et al, 2005), the growth conditions used thus far caused a significant difference in growth rate between the reference and the sfp1D mutant. The transcriptional activity of a cell, ribosome biogenesis, cell size control and cell cycle progression are dependent on the specific growth rate (Castrillo et al, 2007;Regenberg et al, 2006). Since a regulatory role for Sfp1 has been suggested for all these processes (Cipollina et al, 2005;Fingerman et al, 2003;Jorgensen et al, 2002) the study of a slow-growing sfp1D mutant could lead to misleading conclusions.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the role of yeast Sfp1 in ribosome biogenesis and cell size control: a chemostat study

et al. 2008

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Saccharomyces cerevisiae SFP1 promotes transcription of a large cluster of genes involved in ribosome biogenesis. During growth in shake flasks, a mutant deleted for SFP1 shows a small size phenotype and a reduced growth rate. We characterized the behaviour of an sfp1D mutant compared to an isogenic reference strain growing in chemostat cultures at the same specific growth rate. By studying glucose (anaerobic)-and ethanol (aerobic)-limited cultures we focused specifically on nutrient-dependent effects. Major differences in the genome-wide transcriptional profiles were observed during glucose-limited growth. In particular, Sfp1 appeared to be involved in the control of ribosome biogenesis but not of ribosomal protein gene expression. Flow cytometric analyses revealed size defects for the mutant under both growth conditions. Our results suggest that Sfp1 plays a role in transcriptional and cell size control, operating at two different levels of the regulatory network linking growth, metabolism and cell size.

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“…This range was within our typical tolerance of +/-0.01 vol/hr difference from the target setting, beyond which large-scale changes in gene expression have been observed. [22][23] Across 4 ministats the air flow rate was determined to be 307.5 ml/min with a standard deviation of 9.57 ml/min. This suggests that air-flow into the chambers is robust and evenly divided between the 4 chambers and is a value similar to that described for aeration in industrial fermentors.…”

Section: Introductionmentioning

confidence: 99%

Design and Use of Multiplexed Chemostat Arrays

Miller

Befort

Kerr

et al. 2013

JoVE

105

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Chemostats are continuous culture systems in which cells are grown in a tightly controlled, chemically constant environment where culture density is constrained by limiting specific nutrients.1,2 Data from chemostats are highly reproducible for the measurement of quantitative phenotypes as they provide a constant growth rate and environment at steady state. For these reasons, chemostats have become useful tools for fine-scale characterization of physiology through analysis of gene expression [3][4][5][6] and other characteristics of cultures at steady-state equilibrium. 7 Long-term experiments in chemostats can highlight specific trajectories that microbial populations adopt during adaptive evolution in a controlled environment. In fact, chemostats have been used for experimental evolution since their invention. 8 A common result in evolution experiments is for each biological replicate to acquire a unique repertoire of mutations. 9-13 This diversity suggests that there is much left to be discovered by performing evolution experiments with far greater throughput.We present here the design and operation of a relatively simple, low cost array of miniature chemostats-or ministats-and validate their use in determination of physiology and in evolution experiments with yeast. This approach entails growth of tens of chemostats run off a single multiplexed peristaltic pump. The cultures are maintained at a 20 ml working volume, which is practical for a variety of applications. It is our hope that increasing throughput, decreasing expense, and providing detailed building and operation instructions may also motivate research and industrial application of this design as a general platform for functionally characterizing large numbers of strains, species, and growth parameters, as well as genetic or drug libraries.

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Growth control of the eukaryote cell: a systems biology study in yeast

Cited by 250 publications

References 119 publications

Regulatory crosstalk of the metabolic network

Regulatory crosstalk of the metabolic network

Revisiting the role of yeast Sfp1 in ribosome biogenesis and cell size control: a chemostat study

Design and Use of Multiplexed Chemostat Arrays

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