Background: In favorable conditions bacterial doubling time is less than 20 min, shorter than DNA replication time. In E. coli a single round of genome replication lasts about 40 min and it must be accomplished about 20 min before cell division. To achieve such fast growth rates bacteria perform multiple replication rounds simultaneously. As a result, when the division time is as short as 20 min E. coli has about 8 copies of origin of replication (ori) and the average copy number of the genes situated close to ori can be 4 times larger than those near the terminus of replication (ter). It implies that shortening of cell cycle may influence dynamics of regulatory pathways involving genes placed at distant loci.
Results: We analyze this effect in a model of a genetic toggle switch, i.e. a system of two mutually repressing genes, one localized in the vicinity of ori and the other localized in the vicinity of ter. Using a stochastic model that accounts for cell growth and divisions we demonstrate that shortening of the cell cycle can induce switching of the toggle to the state in which expression of the gene placed near ter is suppressed. The toggle bistability causes that the ratio of expression of the competing genes changes more than two orders of magnitude for a two-fold change of the doubling time. The increasing stability of the two toggle states enhances system sensitivity but also its reaction time.
Conclusions: By fusing the competing genes with fluorescent tags this mechanism could be tested and employed to create an indicator of the doubling time. By manipulating copy numbers of the competing genes and locus of the gene situated near ter, one can obtain equal average expression of both genes for any doubling time T between 20 and 120 min. Such a toggle would accurately report departures of the doubling time from T.
Keywords: Bistability; DNA replication; Gene copy number; Mathematical modeling; Regulatory pathways; Stochastic simulations.