Abstract
It has long been noted that batch cultures inoculated with resting bacteria exhibit a progression of growth phases traditionally labeled lag, exponential, pre-stationary and stationary. However, a detailed molecular description of the mechanisms controlling the transitions between these phases is lacking. A core circuit, formed by a subset of regulatory interactions involving five global transcription factors (FIS, HNS, IHF, RpoS and GadX), has been identified by correlating information from the well- established transcriptional regulatory network of Escherichia coli and genome-wide expression data from cultures in these different growth phases. We propose a functional role for this circuit in controlling progression through these phases. Two alternative hypotheses for controlling the transition between the growth phases are first, a continuous graded adjustment to changing environmental conditions, and second, a discontinuous hysteretic switch at critical thresholds between growth phases. We formulate a simple mathematical model of the core circuit, consisting of differential equations based on the power-law formalism, and show by mathematical and computer-assisted analysis that there are critical conditions among the parameters of the model that can lead to hysteretic switch behavior, which – if validated experimentally – would suggest that the transitions between different growth phases might be analogous to cellular differentiation. Based on these provocative results, we propose experiments to test the alternative hypotheses.
Highlights
Biological systems have multiple mechanisms to correctly selfreproduce in a manner compatible with the environment in which they exist
It has been known for some time that bacterial batch cultures tend to follow a well-defined progression of growth phases: lag, exponential, early stationary and stationary [4]
After a century of observations in which culturing bacteria leads to a reproducible progression of growth phases we report a circuit present in the transcriptional regulatory network of E. coli [48] that may be operating behind these visible manifestations of population growth
Summary
Biological systems have multiple mechanisms to correctly selfreproduce in a manner compatible with the environment in which they exist. The design associated with hysteresis appears more likely by inspection of the condition in Eq (5), there has been no empirical evidence to support the existence of a developmental switch-like mechanism governing the progression of growth phases in E. coli To address this issue, we (1) compared the alternative designs for their ability to successfully reproduce known experimental data and (2) provided analytical results that suggest critical experiments to distinguish between the alternatives. The design spaces of the two alternatives exhibit a large number of qualitatively distinct phenotypes that are remarkably similar (same colors), except for the regions of transition (different colors) Taken together, these results suggest that new experimental approaches involving increasing and decreasing titrations in the steady-state level of environmental stresses (such as carbon sources or organic acids), may be necessary for the critical tests required to discriminate between the alternative hypotheses. The reconfiguring of the expression profile for cells deep into the stationary phase or the early lag phase, when there is no growth, can be even longer than the 5 generations associated with growing cells, these responses would undoubted involve down-stream processes that are not part of our current model
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