Mathematical model of the Drosophila circadian clock: loop regulation and transcriptional integration.
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.
Fathallah-Shaykh
Hassan M
HM
The University of Alabama at Birmingham, Department of Neurology, The UAB Comprehensive Neuroscience Center, Birmingham, Alabama, USA. hfathall@uab.edu
Bona
Jerry L
JL
Kadener
Sebastian
S
D000818:Animals; D001683:Biological Clocks; D001703:Biophysics / Q000379:methods; D002940:Circadian Rhythm; D003198:Computer Simulation; D004330:Drosophila / Q000378:metabolism / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D008954:Models, Biological; D008962:Models, Theoretical; D009154:Mutation; D056950:Period Circadian Proteins; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C521952:Cwo protein, Drosophila; D029721:Drosophila Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D012097:Repressor Proteins