title: Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics in Mycobacterium tuberculosis.
abstract: Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the σB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.
authors.affiliation: Department of Bioengineering and Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.
authors.forename: Joao A
authors.initials: JA
authors.lastname: Ascensao
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Pratik
authors.initials: P
authors.lastname: Datta
authors.affiliation: Department of Bioengineering and Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.
authors.forename: Baris
authors.initials: B
authors.lastname: Hancioglu
authors.affiliation: Department of Mathematics and Center for Quantitative Biology, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sontag
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gennaro
authors.affiliation: Department of Bioengineering and Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Igoshin
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D006038:Glyoxylates / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008957:Models, Genetic; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D049490:Systems Biology / Q000379:methods; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D006038:Glyoxylates; D014157:Transcription Factors; C031150:glyoxylic acid