Mathematics Department, British Columbia Institute of Technology, Burnaby, British Columbia, Canada.
PLoS Comput Biol. 2011 Feb 3;7(2):e1001069. doi: 10.1371/journal.pcbi.1001069.
Positional information in developing embryos is specified by spatial gradients of transcriptional regulators. One of the classic systems for studying this is the activation of the hunchback (hb) gene in early fruit fly (Drosophila) segmentation by the maternally-derived gradient of the Bicoid (Bcd) protein. Gene regulation is subject to intrinsic noise which can produce variable expression. This variability must be constrained in the highly reproducible and coordinated events of development. We identify means by which noise is controlled during gene expression by characterizing the dependence of hb mRNA and protein output noise on hb promoter structure and transcriptional dynamics. We use a stochastic model of the hb promoter in which the number and strength of Bcd and Hb (self-regulatory) binding sites can be varied. Model parameters are fit to data from WT embryos, the self-regulation mutant hb(14F), and lacZ reporter constructs using different portions of the hb promoter. We have corroborated model noise predictions experimentally. The results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, rather than on Bcd fluctuations. The constructs and mutant, which lack self-regulation, indicate that the multiple Bcd binding sites in the hb promoter (and their strengths) also play a role in buffering noise. The model is robust to the variation in Bcd binding site number across a number of fly species. This study identifies particular ways in which promoter structure and regulatory dynamics reduce hb output noise. Insofar as many of these are common features of genes (e.g. multiple regulatory sites, cooperativity, self-feedback), the current results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development.
胚胎发育中的位置信息由转录调控因子的空间梯度决定。研究这一现象的经典系统之一是,母体来源的 Bicoid(Bcd)蛋白梯度激活早期果蝇(Drosophila)胚胎中的 hunchback(hb)基因。基因调控受到内在噪声的影响,这种噪声可能会导致表达的可变性。这种可变性必须在高度可重复和协调的发育事件中受到限制。我们通过描述 hb mRNA 和蛋白质输出噪声对 hb 启动子结构和转录动力学的依赖性,确定了在基因表达过程中控制噪声的方法。我们使用 hb 启动子的随机模型,其中 Bcd 和 Hb(自我调节)结合位点的数量和强度可以改变。使用 WT 胚胎、自我调节突变体 hb(14F)和带有不同 hb 启动子部分的 lacZ 报告基因构建体的数据,对模型参数进行拟合。我们通过实验证实了模型噪声预测。结果表明,WT(自我调节)Hb 输出噪声主要取决于其自身表达的转录和翻译动力学,而不是 Bcd 波动。缺乏自我调节的构建体和突变体表明,hb 启动子中的多个 Bcd 结合位点(及其强度)也在缓冲噪声方面发挥作用。该模型对多个果蝇物种中 Bcd 结合位点数量的变化具有鲁棒性。这项研究确定了启动子结构和调节动力学降低 hb 输出噪声的特定方式。由于其中许多是基因的共同特征(例如多个调节位点、协同作用、自我反馈),因此当前的结果有助于人们普遍理解早期发育中空间模式的可重复性和确定性。
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