Entrainment of a Bacterial Synthetic Gene Oscillator through Proteolytic Queueing

Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological systems, and maintenance of a given period and phase among many such oscillators may be important for their proper function. However, both environmental variability and fundamental molecular noise can cause biochemical oscillators to lose coherence. One solution to maintaining coherence is entrainment, where an external signal provides a cue that resets the phase of the oscillators. In this work, we study the entrainment of gene networks by a queueing interaction established by competition between proteins for a common proteolytic pathway. Principles of queueing entrainment are investigated for an established synthetic oscillator in Escherichia coli. We first explore this theoretically using a standard chemical reaction network model and a map-based model, both of which suggest that queueing entrainment can be achieved through pulsatile production of an additional protein competing for a common degradation pathway with the oscillator proteins. We then use a combination of microfluidics and fluorescence microscopy to verify that pulse trains modulating the production rate of a fluorescent protein targeted to the same protease (ClpXP) as the synthetic oscillator can entrain the oscillator.