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


CONCLUSIONS
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.
Castrillo
Juan I
JI
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Zeef
Leo A
LA
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Hoyle
David C
DC
Northwest Institute for Bio-Health Informatics (NIBHI), School of Medicine, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Zhang
Nianshu
N
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Hayes
Andrew
A
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Gardner
David Cj
DC
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Cornell
Michael J
MJ
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|School of Computer Science, Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Petty
June
J
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Hakes
Luke
L
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Wardleworth
Leanne
L
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Rash
Bharat
B
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Brown
Marie
M
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Dunn
Warwick B
WB
Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Broadhurst
David
D
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
O'Donoghue
Kerry
K
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
Hester
Svenja S
SS
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
Dunkley
Tom Pj
TP
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
Hart
Sarah R
SR
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Swainston
Neil
N
Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Li
Peter
P
Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Gaskell
Simon J
SJ
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Paton
Norman W
NW
School of Computer Science, Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Lilley
Kathryn S
KS
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
Kell
Douglas B
DB
School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
Oliver
Stephen G
SG
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
D002244:Carbon / Q000378:metabolism; D018929:Cell Culture Techniques; D005057:Eukaryotic Cells / Q000502:physiology*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D002244:Carbon; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases