Metabolic cycling without cell division cycling in respiring yeast. Proc Natl Acad Sci USA

Departments of Biology and Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2011; 108(47):19090-5. DOI: 10.1073/pnas.1116998108
Source: PubMed


Despite rapid progress in characterizing the yeast metabolic cycle, its connection to the cell division cycle (CDC) has remained unclear. We discovered that a prototrophic batch culture of budding yeast, growing in a phosphate-limited ethanol medium, synchronizes spontaneously and goes through multiple metabolic cycles, whereas the fraction of cells in the G1/G0 phase of the CDC increases monotonically from 90 to 99%. This demonstrates that metabolic cycling does not require cell division cycling and that metabolic synchrony does not require carbon-source limitation. More than 3,000 genes, including most genes annotated to the CDC, were expressed periodically in our batch culture, albeit a mere 10% of the cells divided asynchronously; only a smaller subset of CDC genes correlated with cell division. These results suggest that the yeast metabolic cycle reflects a growth cycle during G1/G0 and explains our previous puzzling observation that genes annotated to the CDC increase in expression at slow growth.

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Available from: Nikolai Slavov
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    • "In the long-period YMC, a single cell alternates between periods of high (oxidative (OX) phase) or low oxygen consumption (reductive building (RB) and charging (RC) phases), the residence time in each phase being nutrient-dependent. For exponentially growing cells in batch culture, the majority of cells in the population will be in the OX phase of the YMC (Slavov et al., 2011). Transcript levels for genes that cycle in the YMC will change as the cell moves through these phases; at any time, some cells in an asynchronous population will contain a transcript and some will not. "
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    ABSTRACT: In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change. DOI:
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    • "With the development of new technologies (such as microfluidics systems with a mass sensor), precise monitoring of cell size has become possible (Son et al. 2012). Considering the ongoing systems biology research on cell growth (Ferrezuelo et al. 2012) and metabolism (Slavov et al. 2011), a better understanding of the interplay between cell growth and division can be expected in the near future. The systems approach can also be used to address epigenetic factors. "
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    ABSTRACT: Cells proliferate by division into similar daughter cells, a process that lies at the heart of cell biology. Extensive research on cell division has led to the identification of the many components and control elements of the molecular machinery underlying cellular division. Here we provide a brief review of prokaryotic and eukaryotic cell division and emphasize how new approaches such as systems and synthetic biology can provide valuable new insight.
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    • "Such a decrease in NADPH production could explain at least in part the decreased stress resistance that we measured (Figures 3D and 3E). This pathway for THF-mediated mitochondrial NADPH production is transcriptional upregulated with the growth rate and increased respiration of yeast growing on ethanol carbon source (Slavov and Botstein, 2011), suggesting its broader significance for respiratory metabolism. "
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    ABSTRACT: Fermentating glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying O2 consumption, CO2 production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration) and of mitochondrial folate-mediated NADPH production (required for oxidative defense). The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival.
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