Construction of genetic oscillators with interlocked feedback networks.

To understand how a gene regulatory network functioning as an oscillator is built, a precise mathematical description of the network and its dynamical properties are developed in this paper. Our approach is based on analyzing the effect of interactions between smaller subnetworks with simple dynamics. We relate an oscillatory behavior of the network to the destabilization phenomenon of a steady state caused by the interactions in a simple discrete map. When source of the instability of the steady state rather than the oscillatory behavior itself is considered, linear stability analysis and feedback control theory can be employed. Moreover, the amplitudes robust against change in delay can also be obtained from the discrete map. The main ideas are illustrated by constructing a genetic oscillator termed a "repressilator" and analyzing the occurrence of cellular rhythms, although the theoretical results hold for a general class of biological systems. The method can be directly applied to design, construct genetic oscillators, and further control their dynamics, even for large-scale networks.