Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK
Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK
复制标题
DOI：
10.1016/s0006-3495(04)74332-5
复制
发表时间：
2004-05-01
影响因子：
3.4
通讯作者：
Byrne, JH
中科院分区：
文献类型：
--
作者：
Smolen, P;Hardin, PE;Byrne, JH
果蝇昼夜节律产生的模型被开发来表示基于per、Clk（dclock）、Pdp-1和vri（vrille）的转录调节的反馈回路。该模型假设组蛋白乙酰化动力学使转录激活成为[CLK]的非线性函数。这样的非线性是必不可少的，以模拟强大的昼夜节律振荡的转录在我们的模型和以前的模型。模拟表明，两个正反馈回路涉及Clk是不是必不可少的振荡，因为振荡[PER]时，Clk，vri，或Pdp-1的表达是固定的。然而，消除积极的反馈。xing vri表达改变了振荡周期。消除PER抑制PER表达的负反馈回路可以消除振荡。模拟的每或Clk无效突变，每过表达，和vri，Clk，或Pdp-1杂合无效突变改变模型的行为类似的方式实验数据。该模型模拟的光的相位响应曲线类似的实验曲线，和振荡夹带模拟光暗周期。如果温度升高减缓PER核进入或PER磷酸化，则可以模拟振荡周期的温度补偿。该模型进行实验预测，其中一些可以在转基因果蝇中进行测试。
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 that 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. However, eliminating positive feedback by. xing vri expression altered the oscillation period. Eliminating the negative feedback loop in which PER represses per expression abolished oscillations. Simulations of per or Clk null mutations, of per overexpression, 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. Temperature compensation of oscillation period could be simulated if temperature elevation slowed PER nuclear entry or PER phosphorylation. The model makes experimental predictions, some of which could be tested in transgenic Drosophila.