Karmakar Rajesh, Bose Indrani
Department of Physics, Bose Institute, Kolkata, India.
Phys Biol. 2006 Sep 28;3(3):200-8. doi: 10.1088/1478-3975/3/3/005.
We consider a stochastic model of transcription factor (TF)-regulated gene expression. The model describes two genes, gene A and gene B, which synthesize the TFs and the target gene proteins, respectively. We show through analytic calculations that the TF fluctuations have a significant effect on the distribution of the target gene protein levels when the mean TF level falls in the highest sensitive region of the dose-response curve. We further study the effect of reducing the copy number of gene A from two to one. The enhanced TF fluctuations yield results different from those in the deterministic case. The probability that the target gene protein level exceeds a threshold value is calculated with the knowledge of the probability density functions associated with the TF and target gene protein levels. Numerical simulation results for a more detailed stochastic model are shown to be in agreement with those obtained through analytic calculations. The relevance of these results in the context of the genetic disorder haploinsufficiency is pointed out. Some experimental observations on the haploinsufficiency of the tumour suppressor gene, Nkx 3.1, are explained with the help of the stochastic model of TF-regulated gene expression.
我们考虑一种转录因子（TF）调控基因表达的随机模型。该模型描述了两个基因，基因A和基因B，它们分别合成转录因子和靶基因蛋白。我们通过解析计算表明，当平均转录因子水平处于剂量反应曲线的最高敏感区域时，转录因子波动对靶基因蛋白水平的分布有显著影响。我们进一步研究了将基因A的拷贝数从两个减少到一个的效果。增强的转录因子波动产生的结果与确定性情况不同。利用与转录因子和靶基因蛋白水平相关的概率密度函数知识，计算靶基因蛋白水平超过阈值的概率。一个更详细的随机模型的数值模拟结果显示与通过解析计算得到的结果一致。指出了这些结果在遗传疾病单倍剂量不足背景下的相关性。借助转录因子调控基因表达的随机模型解释了关于肿瘤抑制基因Nkx 3.1单倍剂量不足的一些实验观察结果。
