Model of the Drosophila Circadian Clock: Loop Regulation and Transcriptional Integration

Circadian clocks influence key features of daily life including timing of sleep, awakening, and feeding. Eukaryoticcircadian clocks include interconnected positive and negative feedback loops. The CLOCK-CYCLE dimer (CLK-CYC) and its homolog, CLK-BMAL1, are key transcriptional activators of central components of the Drosophila and mammalian circadian networks, respectively. In Drosophila, negative loops include period-timeless and vrille; positive loops include par domain protein 1. Clockwork Orange (CWO) is a recently discovered negative transcription factor with unusual effects on period, timeless, vrille, and par domain protein 1. To understand the actions of this protein, we introduced a new system of ordinary differential equations to model regulatory networks. The model is faithful in the sense that it replicates biological observations. CWO loop-actions elevate CLK-CYC; the transcription of direct targets responds by integrating opposing signals from CWO and CLK-CYC. CWO, a transcriptional repressor of direct targets in one-dimensional in vitro experiments, is actually a transcriptional activator in vivo. Loop regulation and integration of opposite transcriptional signals appear to be central mechanisms as they also explain paradoxical effects of period gain-of-function and null mutations.