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

Juan I Castrillo^*¹ , Leo A Zeef^*¹ , David C Hoyle^*² , Nianshu Zhang¹ , Andrew Hayes¹ , David CJ Gardner¹ , Michael J Cornell¹^,3 , June Petty¹ , Luke Hakes¹ , Leanne Wardleworth¹ , Bharat Rash¹ , Marie Brown⁴ , Warwick B Dunn⁶ , David Broadhurst⁴^,6 , Kerry O'Donoghue⁵ , Svenja S Hester⁵ , Tom PJ Dunkley⁵ , Sarah R Hart⁴ , Neil Swainston⁶ , Peter Li⁶ , Simon J Gaskell⁴^,6 , Norman W Paton³^,6 , Kathryn S Lilley⁵ , Douglas B Kell⁴^,6 and Stephen G Oliver¹^,6

¹Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK

²Northwest Institute for Bio-Health Informatics (NIBHI), School of Medicine, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK

³School of Computer Science, Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK

⁴School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK

⁵Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK

⁶Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK

author email corresponding author email* Contributed equally

Journal of Biology 2007, 6:4doi:10.1186/jbiol54


Published:	30 April 2007

Abstract

Background

Cell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking.

Results

Metabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth.

Conclusion

This work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell.