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Biophys J. 2009 Nov 4;97(9):2399-408. doi: 10.1016/j.bpj.2009.08.018.

Mathematical model of the Drosophila circadian clock: loop regulation and transcriptional integration.

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The University of Alabama at Birmingham, Department of Neurology, The UAB Comprehensive Neuroscience Center, Birmingham, Alabama, USA.


Eukaryotic circadian 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. 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.

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