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bioRxiv2014

Dual autogenous control of the multiple antibiotic resistance phenotype in Escherichia coli

Bacteria can defend against diverse antibiotics by mounting a multiple antibiotic resistance (mar) phenotype. The resistance is linked to a chromosomal locus that encodes an activator and a repressor regulating their own expression. Here, we investigated how this dual autogenous control determines the dynamics of the response. We found that the regulatory architecture provides a mechanism to enable rapid induction, generate pulses of activation, and increase the range of sensing. The response is also graded and homogeneous across the population. Moreover, the interaction of a third regulator with the core module fine tunes the previous features, while limiting the cross-talk with metabolic signals. A minimal model accurately anticipates these properties, and emphasizes how specific attributes of the circuit components constrain the appearance of other potential behaviors associated to the regulatory design. Our results integrate both molecular and circuit-level characteristics to fully elucidate the dynamic emergence of the mar phenotype.

Systems Biology↗

bioRxiv2014

Rewiring of genetic networks in response to modification of genetic background

Genome-scale genetic interaction networks are progressively contributing to map the molecular circuitry that determines cellular behaviour. To what extent this mapping changes in response to different environmental or genetic conditions is however largely unknown. Here we assembled a genetic network using an in silico model of metabolism in yeast to explicitly ask how separate genetic backgrounds alter network structure. Backgrounds defined by single deletions of metabolically active enzymes induce strong rewiring when the deletion corresponds to a catabolic gene, evidencing a broad redistribution of fluxes to alternative pathways. We also show how change is more pronounced in interactions linking genes in distinct functional modules, and in those connections that present weak epistasis. These patterns reflect overall the distributed robustness of catabolism. In a second class of genetic backgrounds, in which a number of neutral mutations accumulate, we dominantly observe modifications in the negative interactions that together with an increase in the number of essential genes indicate a global reduction in buffering. Notably, neutral trajectories that originate considerable changes in the wild-type network comprise mutations that diminished the environmental plasticity of the corresponding metabolism, what emphasizes a mechanistic integration of genetic and environmental buffering. More generally, our work demonstrates how the specific mechanistic causes of robustness influence the architecture of multiconditional genetic interaction maps.

Systems Biology↗