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Positive Autoregulation Delays the Expression Phase of Mammalian Clock Gene Per2

Figure 4

A novel model to reproduce the expression phase difference between Per1 and Per2.

(A) A new model hypothesized Per2 positive feedback regulation. Nuclear PER1/2 acts as a positive regulator of Per2 mRNA transcription. Details are described in Text S1 and parameters are indicated in Table S1. (B) A simulation result of the model without the positive feedback regulation (kAP2 = 0 h−1). This model simulated the circadian oscillations in 23.5-hour periods but did not reproduce the oscillation phase of Per1 preceding that of Per2 when applying the measured ratios of the synthesis and degradation rates of Per1 and Per2. The oscillation phase of Per1 lagged behind than that of Per2 by 6.1 hours (6.25 hours in CT). (C) A simulation result of the model with the rate coefficient of positive feedback regulation kAP2 = 2.4 h−1. This model simulated the circadian oscillations in 22.8-hour period and the expression phase of Per2 mRNA was delayed from that of Per1 by 4.0 hours. Arrows indicate expression peaks. After 1000 hours simulation, the first peak of Per1 mRNA was set to simulation time 6.

Figure 4