Observing metabolic functions at the genome scale

BackgroundHigh-throughput techniques have multiplied the amount and the types of available biological data, and for the first time achieving a global comprehension of the physiology of biological cells has become an achievable goal. This aim requires the integration of large amounts of heterogeneous data at different scales. It is notably necessary to extend the traditional focus on genomic data towards a truly functional focus, where the activity of cells is described in terms of actual metabolic processes performing the functions necessary for cells to live.ResultsIn this work, we present a new approach for metabolic analysis that allows us to observe the transcriptional activity of metabolic functions at the genome scale. These functions are described in terms of elementary modes, which can be computed in a genome-scale model thanks to a modular approach. We exemplify this new perspective by presenting a detailed analysis of the transcriptional metabolic response of yeast cells to stress. The integration of elementary mode analysis with gene expression data allows us to identify a number of functionally induced or repressed metabolic processes in different stress conditions. The assembly of these elementary modes leads to the identification of specific metabolic backbones.ConclusionThis study opens a new framework for the cell-scale analysis of metabolism, where transcriptional activity can be analyzed in terms of whole processes instead of individual genes. We furthermore show that the set of active elementary modes exhibits a highly uneven organization, where most of them conduct specialized tasks while a smaller proportion performs multi-task functions and dominates the general stress response.

[1]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[2]  D. Fell,et al.  A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks , 2000, Nature Biotechnology.

[3]  D. Botstein,et al.  Genomic expression programs in the response of yeast cells to environmental changes. , 2000, Molecular biology of the cell.

[4]  B. Palsson,et al.  Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from a pathway-oriented perspective. , 2000, Journal of theoretical biology.

[5]  E. Lander,et al.  Remodeling of yeast genome expression in response to environmental changes. , 2001, Molecular biology of the cell.

[6]  M. Toledano,et al.  A Proteome Analysis of the Cadmium Response in Saccharomyces cerevisiae * , 2001, The Journal of Biological Chemistry.

[7]  M. Marton,et al.  Transcriptional Profiling Shows that Gcn4p Is a Master Regulator of Gene Expression during Amino Acid Starvation in Yeast , 2001, Molecular and Cellular Biology.

[8]  S. Shen-Orr,et al.  Networks Network Motifs : Simple Building Blocks of Complex , 2002 .

[9]  M E J Newman,et al.  Community structure in social and biological networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[11]  Thomas Pfeiffer,et al.  Exploring the pathway structure of metabolism: decomposition into subnetworks and application to Mycoplasma pneumoniae , 2002, Bioinform..

[12]  Benno Schwikowski,et al.  Discovering regulatory and signalling circuits in molecular interaction networks , 2002, ISMB.

[13]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[14]  Albert-László Barabási,et al.  Linked: The New Science of Networks , 2002 .

[15]  A. Barabasi,et al.  Hierarchical Organization of Modularity in Metabolic Networks , 2002, Science.

[16]  Daniel Hanisch,et al.  Co-clustering of biological networks and gene expression data , 2002, ISMB.

[17]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. Palsson,et al.  An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR) , 2003, Genome Biology.

[19]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Palsson,et al.  Constraints-based models: regulation of gene expression reduces the steady-state solution space. , 2003, Journal of theoretical biology.

[21]  Albert-László Barabási,et al.  Aggregation of topological motifs in the Escherichia coli transcriptional regulatory network , 2004, BMC Bioinformatics.

[22]  Jason A. Papin,et al.  Metabolic pathways in the post-genome era. , 2003, Trends in biochemical sciences.

[23]  K. Buetow,et al.  A computational approach to measuring coherence of gene expression in pathways. , 2004, Genomics.

[24]  J. Stelling,et al.  Combinatorial Complexity of Pathway Analysis in Metabolic Networks , 2004, Molecular Biology Reports.

[25]  Sergei Maslov,et al.  Detection of topological patterns in protein networks. , 2004, Genetic engineering.

[26]  Alexis Groppi,et al.  New strategy for the representation and the integration of biomolecular knowledge at a cellular scale. , 2004, Nucleic acids research.

[27]  Lan V. Zhang,et al.  Evidence for dynamically organized modularity in the yeast protein–protein interaction network , 2004, Nature.

[28]  Peter D Wentzell,et al.  Genomic analysis of stationary-phase and exit in Saccharomyces cerevisiae: gene expression and identification of novel essential genes. , 2004, Molecular biology of the cell.

[29]  Steffen Klamt,et al.  Computation of elementary modes: a unifying framework and the new binary approach , 2004, BMC Bioinformatics.

[30]  David Y. Thomas,et al.  Cold adaptation in budding yeast. , 2004, Molecular biology of the cell.

[31]  Markus J. Herrgård,et al.  Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. , 2004, Genome research.

[32]  Shuji Ishihara,et al.  Cross talking of network motifs in gene regulation that generates temporal pulses and spatial stripes , 2005, Genes to cells : devoted to molecular & cellular mechanisms.

[33]  Jochen Förster,et al.  Modeling Lactococcus lactis using a genome-scale flux model , 2005, BMC Microbiology.

[34]  Steffen Klamt,et al.  A methodology for the structural and functional analysis of signaling and regulatory networks , 2006, BMC Bioinformatics.

[35]  Anne Kümmel,et al.  In silico genome-scale reconstruction and validation of the Staphylococcus aureus metabolic network. , 2005, Biotechnology and bioengineering.

[36]  J P Mazat,et al.  Pathway classification of TCA cycle. , 2006, Systems biology.

[37]  Bernhard O. Palsson,et al.  Matrix Formalism to Describe Functional States of Transcriptional Regulatory Systems , 2006, PLoS Comput. Biol..

[38]  Maqc Consortium.  The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements , 2006, Nature Biotechnology.

[39]  D. Kell.  Systems biology, metabolic modelling and metabolomics in drug discovery and development. , 2006, Drug discovery today.

[40]  Andrey A Mironov,et al.  A metabolic network in the evolutionary context: multiscale structure and modularity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Kiyoko F. Aoki-Kinoshita,et al.  From genomics to chemical genomics: new developments in KEGG , 2005, Nucleic Acids Res..

[42]  A. Loraine,et al.  Transcriptional Coordination of the Metabolic Network in Arabidopsis1[W][OA] , 2006, Plant Physiology.