title: Top-level dynamics and the regulated gene response of feed-forward loop transcriptional motifs.
abstract: Feed-forward loops are hierarchical three-node transcriptional subnetworks, wherein a top-level protein regulates the activity of a target gene via two paths: a direct-regulatory path, and an indirect route, whereby the top-level proteins act implicitly through an intermediate transcription factor. Using a transcriptional network of the model bacterium Escherichia coli, we confirmed that nearly all types of feed-forward loop were significantly overrepresented in the bacterial network. We then used mathematical modeling to study their dynamics by manipulating the rise times of the top-level protein concentration, termed the induction time, through alteration of the protein destruction rates. Rise times of the regulated proteins exhibited two qualitatively different regimes, depending on whether top-level inductions were "fast" or "slow." In the fast regime, rise times were nearly independent of rapid top-level inductions, indicative of biological robustness, and occurred when RNA production rate-limits the protein yield. Alternatively, the protein rise times were dependent upon slower top-level inductions, greater than approximately one bacterial cell cycle. An equation is given for this crossover, which depends upon three parameters of the direct-regulatory path: transcriptional cooperation at the DNA-binding site, a protein-DNA dissociation constant, and the relative magnitude of the top-level protien concentration.
authors.affiliation: Environmental Laboratory, US Army Engineer Research and Development Center, Vicksburg, Mississippi 39180, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mayo
authors.affiliation: Department of Computer Science, Virginia Commonwealth University, Richmond, Virginia 23284, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelzaher
authors.affiliation: Environmental Laboratory, US Army Engineer Research and Development Center, Vicksburg, Mississippi 39180, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Perkins
authors.affiliation: Department of Computer Science, Virginia Commonwealth University, Richmond, Virginia 23284, USA.
authors.forename: Preetam
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D004926:Escherichia coli / Q000235:genetics; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008957:Models, Genetic; D014176:Protein Biosynthesis; D014158:Transcription, Genetic