Stoichiometric constraint-based modelling of the yeast metabolic oscillator

Douglas Brian MURRAY

Institute for Advanced Biosciences, Keio University, JP

Abstract


   The metabolic network is the primary driver for cellular dynamics. The vast majority of research has focussed on isolated sub-systems of the metabolic network, leading to great advances in our understanding of their biochemical and genetic regulation of these sub-systems. Bakers' yeast has been at the forefront of this research, leading to perhaps the most comprehensive biochemical network model for any organism[1]. However, our holistic understanding of metabolic dynamics remains poor, partly because of the mushrooming complexity of biochemical systems. Our group primarily uses the autonomous metabolic oscillator that emerges during continuously grown yeast cultures to probe cellular dynamics in precisely defined environments[2,3]. During the oscillation the cell-division cycle[4,5], metabolome[6,7], transcriptome[5,8,9] and chromatin state[1012] show specific phase relationships with respiratory activity. Here, I will present our efforts to integrating these data with dynamical constraint-based modelling, specifically a dynamical Flux Balance Analysis (Shüki FBA). I will elaborate on the self-organisation of catabolism and anabolism, the under appreciated role for carbon dioxide fixation in yeast, methods to predict the temporal profiles of metabolites, and future directions and challenges for modelling dynamical systems.

References

1. Dobson PD, Smallbone K, Jameson D, Simeonidis E, Lanthaler K, Pir PP, et al. Further developments towards a genome-scale metabolic model of yeast. BMC Syst Biol. 2010;4: 145.

2. Finn RK, Wilson RE. Fermentation Process Control, Population Dynamics of a Continuous Propagator for Microorganisms. J Agri Food Chem. American Chemical Society 1954;2: 66--69.

3. Keulers M, Suzuki T, Satroutdinov AD, Kuriyama H. Autonomous metabolic oscillation in continuous culture of Saccharomyces cerevisiae grown on ethanol. FEMS Microbiol. Lett. 1996;142: 253--258.

4. von Meyenburg HK. Energetics of the budding cycle of Saccharomyces cerevisiae during glucose limited aerobic growth. Arch Microbiol. 1969;66: 289--303.

5. Klevecz RR, Bolen J, Forrest G, Murray DB. A genomewide oscillation in transcription gates DNA replication and cell cycle. Proc. Natl. Acad. Sci. U S A. 2004;101: 1200--5.

6. Murray DB, Beckmann M, Kitano H. Regulation of yeast oscillatory dynamics. Proc. Acad. Sci. U S A. 2007;104.

7. Sasidharan K, Soga T, Tomita M, Murray DB. A Yeast Metabolite Extraction Protocol Optimised for Time-Series Analyses. Tuite MF, editor. PLoS One. Public Library of Science 2012;7: e44283.

8. Tu BP, Kudlicki A, Rowicka M, McKnight SL. Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. Science. 2005;310: 1152--8.

9. Slavov N, Macinskas J, Caudy A, Botstein D. Metabolic cycling without cell division cycling in respiring yeast. Proc. Natl. Acad. Sci. U S A. 2011;108: 19090--19095.

10. Machné R, Murray DB. The Yin and Yang of Yeast Transcription: Elements of a Global Feedback System between Metabolism and Chromatin. Saks V, editor. PLoS One. Public Library of Science 2012;7: e37906.

11. Amariei C, Machné R, Stolc V, Soga T, Tomita M, Murray DB. Time resolved DNA occupancy dynamics during the respiratory oscillation uncover a global reset point in the yeast growth program. Microb. Cell. Shared Science Publishers 2014;1: 279--288.

12. Nocetti N, Whitehouse I. Nucleosome repositioning underlies dynamic gene expression. Genes Dev. 2016;30: 660--672

1.	Dobson PD, Smallbone K, Jameson D, Simeonidis E, Lanthaler K, Pir PP, et al. Further developments towards a genome-scale metabolic model of yeast. BMC Syst Biol. 2010;4: 145.
2.	Finn RK, Wilson RE. Fermentation Process Control, Population Dynamics of a Continuous Propagator for Microorganisms. J Agri Food Chem. American Chemical Society 1954;2: 66--69.
3.	Keulers M, Suzuki T, Satroutdinov AD, Kuriyama H. Autonomous metabolic oscillation in continuous culture of Saccharomyces cerevisiae grown on ethanol. FEMS Microbiol. Lett. 1996;142: 253--258.
4.	von Meyenburg HK. Energetics of the budding cycle of Saccharomyces cerevisiae during glucose limited aerobic growth. Arch Microbiol. 1969;66: 289--303.
5.	Klevecz RR, Bolen J, Forrest G, Murray DB. A genomewide oscillation in transcription gates DNA replication and cell cycle. Proc. Natl. Acad. Sci. U S A. 2004;101: 1200--5.
6.	Murray DB, Beckmann M, Kitano H. Regulation of yeast oscillatory dynamics. Proc. Acad. Sci. U S A. 2007;104.
7.	Sasidharan K, Soga T, Tomita M, Murray DB. A Yeast Metabolite Extraction Protocol Optimised for Time-Series Analyses. Tuite MF, editor. PLoS One. Public Library of Science 2012;7: e44283.
8.	Tu BP, Kudlicki A, Rowicka M, McKnight SL. Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. Science. 2005;310: 1152--8.
9.	Slavov N, Macinskas J, Caudy A, Botstein D. Metabolic cycling without cell division cycling in respiring yeast. Proc. Natl. Acad. Sci. U S A. 2011;108: 19090--19095.
10.	Machné R, Murray DB. The Yin and Yang of Yeast Transcription: Elements of a Global Feedback System between Metabolism and Chromatin. Saks V, editor. PLoS One. Public Library of Science 2012;7: e37906.
11.	Amariei C, Machné R, Stolc V, Soga T, Tomita M, Murray DB. Time resolved DNA occupancy dynamics during the respiratory oscillation uncover a global reset point in the yeast growth program. Microb. Cell. Shared Science Publishers 2014;1: 279--288.
12.	Nocetti N, Whitehouse I. Nucleosome repositioning underlies dynamic gene expression. Genes Dev. 2016;30: 660--672