Network features of the mammalian circadian clock.
Network features of the mammalian circadian clock.
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DOI：
10.1371/journal.pbio.1000052
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发表时间：
2009-03-10
期刊：
影响因子：
9.8
通讯作者：
Hogenesch JB
中科院分区：
文献类型：
--
作者：
Baggs JE;Price TS;DiTacchio L;Panda S;Fitzgerald GA;Hogenesch JB
哺乳动物的生物钟是一个细胞自主系统，它在预期日常环境变化的情况下驱动行为和生理的振荡。为了评估人类分子钟的鲁棒性，我们系统地耗尽了已知的时钟组件，并观察到昼夜节律振荡在广泛的中断范围内保持。我们开发了一种称为基因剂量网络分析（GDNA）的新策略，其中小干扰RNA（siRNA）诱导的基因表达的剂量依赖性变化被用来建立与已知的生物化学约束一致的基因关联网络。多剂量的使用为分析提供了动力，揭示了生物钟的几个新的网络特征，包括比例响应和通过相互作用的遗传模块的信号传播。我们还观察到几个例子，其中一个基因是上调后敲除其parkingdown，这表明时钟网络利用主动补偿机制，而不是简单的冗余，以赋予鲁棒性和维持功能。我们建议，这些网络功能作为一个遗传缓冲系统，以保持时钟功能，面对遗传和环境的扰动。昼夜节律钟是在整个身体中发现的生物钟，它以24小时的节奏协调分子和细胞过程的时间。它由许多反馈和控制自身表达的转录因子组成。为了探索生物钟在面对遗传干扰时如何发挥作用，我们通过以剂量依赖性方式敲低已知生物钟基因的基因表达来破坏其功能。我们测量了敲除后时钟基因的表达，并构建了基于扰动的网络模型来描述、可视化和挖掘结果。我们报告了几个新的网络功能，如通过相互作用的遗传模块和比例响应的信号传播，从而表达水平随基因水平的变化而改变。我们还观察到几个例子，其中一个基因是上调后敲除其parkingdown，这表明时钟网络利用主动补偿机制，而不是简单的冗余，以赋予鲁棒性和维持功能。我们建议，我们观察到的网络功能作为一个遗传缓冲系统，以保持时钟功能，面对遗传和环境的扰动。生物钟如何在基因干扰下保持功能？作者构建了基因剂量扰动网络，并揭示了有助于生物钟遗传缓冲的几个基本原理。
The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. To assess the robustness of a human molecular clock, we systematically depleted known clock components and observed that circadian oscillations are maintained over a wide range of disruptions. We developed a novel strategy termed Gene Dosage Network Analysis (GDNA) in which small interfering RNA (siRNA)-induced dose-dependent changes in gene expression were used to build gene association networks consistent with known biochemical constraints. The use of multiple doses powered the analysis to uncover several novel network features of the circadian clock, including proportional responses and signal propagation through interacting genetic modules. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that these network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation. The circadian clock is the biological clock found throughout the body that coordinates the timing of molecular and cellular processes on a 24-hour rhythm. It is composed of numerous transcription factors that feed back and control their own expression. To explore how the clock functions in the face of genetic perturbations, we disrupted its function by knocking down gene expression of known clock genes in a dose-dependent fashion. We measured the expression of clock genes following knockdown and constructed perturbation-based network models to describe, visualize, and mine the results. We reported several novel network features, such as signal propagation through interacting genetic modules and proportional responses whereby levels of expression are altered commensurately with changing levels of the gene. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that the network features we observe act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation. How does the circadian clock maintain function in the face of genetic perturbation? The authors construct gene dosage perturbation networks and uncover several underlying principles contributing to genetic buffering of the clock.
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影响因子：
56.9
作者：
Ishii, Nobuyoshi;Nakahigashi, Kenji;Tomita, Masaru
通讯作者：
Tomita, Masaru
影响因子：
4.5
作者：
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通讯作者：
Kay SA
DOI：
10.1073/pnas.0604883103
发表时间：
2006-08-01
影响因子：
11.1
作者：
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通讯作者：
Pilpel, Yitzhak
影响因子：
5.8
作者：
Price, Tom S.;Baggs, Julie E.;Hogenesch, John B.
通讯作者：
Hogenesch, John B.
影响因子：
56.9
作者：
Reick, M;Garcia, JA;McKnight, SL
通讯作者：
McKnight, SL