Effects of Population Dynamics on Establishment of a Restriction-Modification System in a Bacterial Host

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-01, Vol.24 (1), p.198
• Main Authors: Graovac, Stefan, Rodic, Andjela, Djordjevic, Magdalena, Severinov, Konstantin, Djordjevic, Marko
• Format: Article
• Language: English
• Subjects: Bacteria; Bacteria - chemistry; Bacteria - genetics; bacterial population dynamics; Binding sites; Cell division; Cell Division - genetics; DNA Replication - genetics; Equilibrium; Experiments; Gene expression; gene expression control; Gene Expression Regulation; Gene regulation; Intracellular; Kinetics; Modelling; Models, Biological; Physiology; Plasmids; Plasmids - genetics; Population; Population Dynamics; Protein expression; Proteins; Restriction-modification; restriction-modification systems; RNA polymerase; statistical thermodynamics; Synthetic biology; Thermodynamics; transcription regulation
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24010198

In vivo dynamics of protein levels in bacterial cells depend on both intracellular regulation and relevant population dynamics. Such population dynamics effects, e.g., interplay between cell and plasmid division rates, are, however, often neglected in modeling gene expression regulation. Including them in a model introduces additional parameters shared by the dynamical equations, which can significantly increase dimensionality of the parameter inference. We here analyse the importance of these effects, on a case of bacterial restriction-modification (R-M) system. We redevelop our earlier minimal model of this system gene expression regulation, based on a thermodynamic and dynamic system modeling framework, to include the population dynamics effects. To resolve the problem of effective coupling of the dynamical equations, we propose a "mean-field-like" procedure, which allows determining only part of the parameters at a time, by separately fitting them to expression dynamics data of individual molecular species. We show that including the interplay between kinetics of cell division and plasmid replication is necessary to explain the experimental measurements. Moreover, neglecting population dynamics effects can lead to falsely identifying non-existent regulatory mechanisms. Our results call for advanced methods to reverse-engineer intracellular regulation from dynamical data, which would also take into account the population dynamics effects.