Design principles of a genetic alarm clock.

Turning genes on and off is a mechanism by which cells and tissues make phenotypic decisions. Gene network motifs capable of supporting two or more steady states and thereby providing cells with a plurality of possible phenotypes are referred to as genetic switches. Modeled on the bases of naturally occurring genetic networks, synthetic biologists have successfully constructed artificial switches, thus opening a door to new possibilities for improvement of the known, but also the design of new synthetic genetic circuits. One of many obstacles to overcome in such efforts is to understand and hence control intrinsic noise which is inherent in all biological systems. For some motifs the noise is negligible; for others, fluctuations in the particle number can be comparable to its average. Due to their slowed dynamics, motifs with positive autoregulation tend to be highly sensitive to fluctuations of their chemical environment and are in general very noisy, especially during transition (switching). In this article we use stochastic simulations (Gillespie algorithm) to model such a system, in particular a simple bistable motif consisting of a single gene with positive autoregulation. Due to cooperativety, the dynamical behavior of this kind of motif is reminiscent of an alarm clock - the gene is (nearly) silent for some time after it is turned on and becomes active very suddenly. We investigate how these sudden transitions are affected by noise and show that under certain conditions accurate timing can be achieved. We also examine how promoter complexity influences the accuracy of this timing mechanism.