Abstract
By integrating positive and negative feedback loops, biological systems establish intricate gene expression patterns linked to multistability, pulsing, and oscillations. This depends on the specific characteristics of each interlinked feedback, and thus one would expect additional expression programs to be found. Here, we investigate one such program associated with an antagonistic positive and negative transcriptional autoregulatory motif derived from the multiple antibiotic resistance (mar) system of Escherichia coli. We studied the dynamics of the system by combining a predictive mathematical model with high-resolution experimental measures of the response both at the population and single-cell level. We show that in this motif the weak positive autoregulation does not slow down but rather enhances response speedup in combination with a strong negative feedback loop. This balance of feedback strengths anticipates a homogeneous population phenotype, which we corroborate experimentally. Theoretical analysis also emphasized the specific molecular properties that determine the dynamics of the mar phenotype. More broadly, response acceleration could provide a rationale for the presence of weak positive feedbacks in other biological scenarios exhibiting these interlinked regulatory architectures.
Highlights
The plastic expression of alternative phenotypes enables Escherichia coli to adjust to many environmental circumstances[1]
We currently recognize that the mar phenotype is coupled to a unique operon architecture harboring a repressor (MarR) and an activator (MarA), and that it is modulated by other transcriptional factors (e.g., SoxS or Rob)[4,5,6]
We initially studied the deterministic dynamics of the mar response with a bottom-up mathematical model and associated nominal parameter values (Methods and Table S1, see Fig. S1 for a parameter sensitivity analysis of the model)
Summary
The plastic expression of alternative phenotypes enables Escherichia coli to adjust to many environmental circumstances[1]. One of these physiological programs corresponds to the multiple antibiotic resistance (mar) phenotype, which capacitates bacteria to tolerate several toxins including antibiotics like tetracycline or chloramphenicol[3] That this response connected for the first time antibiotic resistance to the bacterial chromosome, rather than being caused by a plasmid-borne gene, prompted the search for a better understanding of its genetic architecture. Very little is known about the dynamic aspects of the mar response, and how these aspects are determined by the particular genetic circuit that governs its action This circuit incorporates two feedback loops (Fig. 1) involving a crucial combination of both negative and positive autoregulation ( termed as autogenous control[11,12]). Our study provides a good example of a relatively unexplored dynamical regime within the class of coupled positive/negative feedback architectures[17,18,19,20,21] in which the strength of the positive loop is comparatively weak, what can represent a general design principle at work in other biological contexts
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