Genome-scale integrative data analysis and modeling of dynamic processes in yeast.

Building a dynamic model of a complete biological cell is one of the great challenges of the 21st century. While this objective could appear unrealistic until recently, considerable improvements in high-throughput data collection techniques, computational performance, data integration, and modeling approaches now allow us to consider it within reach in the near future. In this chapter, we review recent developments that pave the way toward the construction of genome-scale dynamic models. We first describe methodologies for the integration of heterogeneous "omics" datasets, which enable the interpretation of cellular activity at the genome scale and in fluctuating conditions, providing the necessary input to models. We subsequently discuss principles of such models and describe a series of approaches that open perspectives toward the construction of genome-scale dynamic models.

Observing metabolic functions at the genome scale.

BACKGROUND: High-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. RESULTS: In 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. CONCLUSION: This 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.