Letters to Nature

Nature 431, 308-312 (16 September 2004) | doi:10.1038/nature02782; Received 15 January 2004; Accepted 24 June 2004

Genomic analysis of regulatory network dynamics reveals large topological changes

Nicholas M. Luscombe1,5, M. Madan Babu4,5, Haiyuan Yu1, Michael Snyder2, Sarah A. Teichmann4 & Mark Gerstein1,3

  1. Department of Molecular Biophysics and Biochemistry, Yale University, PO Box 208114, New Haven, Connecticut 06520-8114, USA
  2. Department of Molecular, Cellular and Developmental Biology, Yale University, PO Box 208114, New Haven, Connecticut 06520-8114, USA
  3. Department of Computer Science, Yale University, PO Box 208114, New Haven, Connecticut 06520-8114, USA
  4. Division of Structural Studies, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
  5. These authors contributed equally to this work

Correspondence to: Nicholas M. Luscombe1,5M. Madan Babu4,5Sarah A. Teichmann4Mark Gerstein1,3 Email: sandy@bioinfo.mbb.yale.edu

Network analysis has been applied widely, providing a unifying language to describe disparate systems ranging from social interactions to power grids. It has recently been used in molecular biology, but so far the resulting networks have only been analysed statically1, 2, 3, 4, 5, 6, 7, 8. Here we present the dynamics of a biological network on a genomic scale, by integrating transcriptional regulatory information9, 10, 11 and gene-expression data12, 13, 14, 15, 16 for multiple conditions in Saccharomyces cerevisiae. We develop an approach for the statistical analysis of network dynamics, called SANDY, combining well-known global topological measures, local motifs and newly derived statistics. We uncover large changes in underlying network architecture that are unexpected given current viewpoints and random simulations. In response to diverse stimuli, transcription factors alter their interactions to varying degrees, thereby rewiring the network. A few transcription factors serve as permanent hubs, but most act transiently only during certain conditions. By studying sub-network structures, we show that environmental responses facilitate fast signal propagation (for example, with short regulatory cascades), whereas the cell cycle and sporulation direct temporal progression through multiple stages (for example, with highly inter-connected transcription factors). Indeed, to drive the latter processes forward, phase-specific transcription factors inter-regulate serially, and ubiquitously active transcription factors layer above them in a two-tiered hierarchy. We anticipate that many of the concepts presented here—particularly the large-scale topological changes and hub transience—will apply to other biological networks, including complex sub-systems in higher eukaryotes.


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