  A model of Drosophila circadian rhythm generation was developed to represent
feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1,
and vri (vrille). The model postulates that histone acetylation kinetics make
transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity
is essential to simulate robust circadian oscillations of transcription in our
model and in previous models. Simulations suggest two positive feedback loops
involving Clk are not essential for oscillations, because oscillations of [PER]
were preserved when Clk, vri, or Pdp-1 expression was fixed. Eliminating the
negative feedback loop in which PER represses per expression abolished
oscillations. Simulations of per or Clk null mutations and of vri, Clk, or
Pdp-1 heterozygous null mutations altered model behavior in ways similar to
experimental data. The model simulated a photic phase-response curve resembling
experimental curves, and oscillations entrained to simulated light-dark cycles.
The model makes experimental predictions, some of which could be tested in
transgenic Drosophila.
