Wang Yong, Zhang Xiang-Sun, Chen Luonan
Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, People's Republic of China.
OMICS. 2009 Aug;13(4):313-24. doi: 10.1089/omi.2009.0040.
Circadian rhythm is fundamentally important in physiological processes of mammals. To reveal its underlying mechanism, we probed functional interactions among genes, motivated by the basic molecular observation on gene expression data in circadian rhythm that a large number of genes oscillate in a coordinated manner. In this study, a reverse-engineering strategy was applied to infer and analyze the structure and function of a circadian rhythm-related gene regulatory network. Specifically, our method integrated four phase-shift time-course gene expression datasets in rat suprachiasmatic nucleus, protein-protein interactions, phosphorylations of a set of key circadian genes, and prior information of cis-regulatory elements, to construct the gene regulatory network related to circadian rhythm of the rat. By follow-up analysis, we identified four new regulatory hubs that may play crucial roles in the regulation of circadian rhythm. Furthermore, we found that feedback loop motifs were significantly enriched in the predicted network, which may contribute to the genome-wide oscillations of the circadian clock. Compared to the small-scale gene regulatory network conducted by experimental method, our study provides a system-wide overview on the gene regulations, which not only reveals the global network structure but also gives valuable insights into the essential mechanism of circadian rhythm.
昼夜节律在哺乳动物的生理过程中至关重要。为揭示其潜在机制，我们受昼夜节律基因表达数据的基本分子观察结果（即大量基因以协调方式振荡）的启发，探究了基因之间的功能相互作用。在本研究中，应用了一种逆向工程策略来推断和分析与昼夜节律相关的基因调控网络的结构和功能。具体而言，我们的方法整合了大鼠视交叉上核中的四个相移时间进程基因表达数据集、蛋白质 - 蛋白质相互作用、一组关键昼夜节律基因的磷酸化以及顺式调控元件的先验信息，以构建与大鼠昼夜节律相关的基因调控网络。通过后续分析，我们鉴定出四个可能在昼夜节律调节中起关键作用的新调控枢纽。此外，我们发现反馈环基序在预测网络中显著富集，这可能有助于昼夜节律钟在全基因组范围内的振荡。与通过实验方法构建的小规模基因调控网络相比，我们的研究提供了关于基因调控的全系统概述，不仅揭示了全局网络结构，还对昼夜节律的基本机制提供了有价值的见解。
