A network of transcriptionally coordinated functional modules in Saccharomyces cerevisiae

Abstract

Recent computational and experimental work suggests that functional modules underlie much of cellular physiology and are a useful unit of cellular organization from the perspective of systems biology. Because interactions among modules can give rise to higher-level properties that are essential to cellular function, a complete knowledge of these interactions is necessary for future work in systems biology, including in silico modeling and metabolic engineering. Here we present a computational method for the systematic identification and analysis of functional modules whose activity is coordinated at the level of transcription. We applied this method, Search for Pairwise Interactions (SPIN), to obtain a global view of functional module connectivity in Saccharomyces cerevisiae and to provide insight into the biological mechanisms underlying this coordination. We also examined this global network at higher resolution to obtain detailed information about the interactions of particular module pairs. For instance, our results reveal possible transcriptional coordination of glycolysis and lipid metabolism by the transcription factor Gcr1p, and further suggest that glycolysis and phosphoinositide signaling may regulate each other reciprocally.[Supplemental material is available online at www.genome.org.]The phenotype of a unicellular organism is determined by an integrated network of genes, proteins, and metabolites that participate in reciprocal regulatory relationships. Creating a quantitative description of this network-a goal that has recently engendered the dedicated discipline of systems biology-is essential to understanding, predicting, and manipulating cellular behavior. A first step toward this goal is deciphering the connectivity of the network, that is, the pattern of interactions among its components. Given the complexity of this undertaking, the integrated network is often treated as a group of superimposed subnetworks, including the gene regulatory, protein, and metabolic networks. A corollary task is to determine whether the network's topology reflects its organizational principles. Using biological networks with relatively well-characterized connectivity, quantitative analyses of network topology have revealed that these networks are modular-they can be clustered into nodes that are more densely connected to each other than to nodes in other clusters (Ravasz et al.

Comprehensive Analysis of Combinatorial Regulation using the Transcriptional Regulatory Network of Yeast

“…42 For instance, the largest module with 23 TFs (Figure 7(a)), has transcription factors that are the key regulators of the core proteins in carbon and nitrogen metabolism (amino acids, sugars and nucleotides), as well as other TFs involved in oxidative and xenobiotic stress responses. This suggests that it might represent a major integrative feature of the yeast transcriptional program that allows the cross-talk between multiple distinct pathways central to growth.…”

Integrative Approach for Detection of Functional Modules from Protein-Protein Interaction Networks

“…The structure of such networks has been frequently analysed to identify the modules, which constitute the basic "building blocks" of molecular networks. One of the challenges that systems biology is facing consists of explaining biological organisation in the light of the existence of modules in networks (Han et al, 2004;PereiraLeal et al, 2004;Petti and Church, 2005;Rives and Galitski, 2003). A series of studies attempting to reveal the modules in cellular networks, ranging from metabolic (Ravasz et al, 2002), to protein networks (Spirin and Mirny, 2003;Yook et al, 2004), support the proposal that modular architecture is one of the principles underlying biological organisation.…”

“…It is further pointed out by Qi and Ge (2006) that the existence of the links between modules emphasises the coordination of the cellular processes. For example, Petti and Church (2005) investigated possible transcriptional coordination between glycolysis and lipid metabolism modules.…”

“…"Modularity is a fundamental design principle whereby components are partitioned according to common physical, regulatory, or functional properties" (Petti and Church, 2005). Modules can be found in many systems, for example, food webs, networks of web pages describing related subjects (Flake et al, 2002), networks of friends in sociology (Newman, 2003), or scientific collaboration networks (Newman, 2001).…”

Models and computational strategies linking physiological response to molecular networks from large-scale data

“…Independence, however, does not require intermodular connections to be weak or unimportant (Watson & Pollack 2005). Connections between functional modules may be critical to the behaviour of the system and represent the integration of multiple sources of information (Hartwell et al 1999;Petti & Church 2005). Moreover, independence does not imply that modules are nonoverlapping, since some genes, proteins and metabolites may be associated to different functions by being part of alternative molecular pathways.…”