Tuning the mammalian circadian clock: robust synergy of two loops.
Tuning the mammalian circadian clock: robust synergy of two loops.
复制标题
调整哺乳动物昼夜节律的时钟：两个循环的强大协同作用。
DOI：
10.1371/journal.pcbi.1002309
复制
发表时间：
2011-12
影响因子：
4.3
通讯作者：
Herzel H
中科院分区：
文献类型：
--
作者：
Relógio A;Westermark PO;Wallach T;Schellenberg K;Kramer A;Herzel H
在大多数生物体中，生物钟负责调节内部节律。它可以预测白天的环境变化，更好地适应生理过程。哺乳动物的主时钟位于视交叉上核（SCN），并与全身的次级时钟同步。它的分子成分形成一个细胞内网络，决定昼夜节律时间并调节生物钟控制的基因。这些生物钟控制的基因参与了重要的生物过程，包括代谢和细胞周期调节。它的故障会导致生物节律的中断，并对生物体造成严重损害。控制昼夜节律系统的详细机制尚未完全了解。数学模型对探索昼夜节律回路的机制有很大的帮助。我们利用从广泛的文献检索中获得的时钟组件的相位和振幅的可用数据建立了核心时钟系统的数学模型。这个模型被用来回答复杂的问题，例如：Per的降解率如何影响系统的周期，ROR/Bmal/REV-ERB （RBR）回路的作用是什么？我们的研究结果表明，时钟基因周期（Per）的RNA降解率的增加可以导致周期的增加或减少——这是我们的模型确定的Per转录物稳定性对昼夜节律周期的非单调效应的结果。此外，我们为RBR环路作为一个独立振荡器的潜在作用提供了理论证据。我们对RBR环的成员进行了过表达实验，导致与我们预测一致的振荡损失。这些发现挑战了RBR环仅仅作为辅助环的作用，并可能改变我们对时钟分子电路和核受体（REV-ERB和ROR）作为分子振荡的假定驱动力的功能的看法。大多数生物体已经进化出一个内部时钟，使它们能够预测和反应每天的昼夜节律，并能够以大约24小时的节奏产生振荡。涉及反馈回路的分子网络负责节律的产生。大量的生物钟控制基因传递时间信息并控制一些生物过程。尽管具有重要的医学意义（在癌症、睡眠障碍、糖尿病和其他疾病中的作用），但生物钟的作用机制及其组成部分的反馈回路的作用仍部分未知。使用数学模型，我们能够对开放的昼夜节律生物学问题提出见解。首先，提高Per的mRNA降解率可能导致周期的增加或减少，这可能解释了实验结果的矛盾。其次，我们的数据指出了ROR/Bmal/REV-ERB循环更相关的作用。特别地，这个回路可以自己是一个振荡器。我们提供的实验证据表明，ROR/Bmal/REV-ERB成员的过表达导致Bmal报告mRNA振荡的丧失。REV-ERB和ROR是核受体，因此在许多细胞过程中具有重要的调节作用，这一事实可能对分子生物学和医学具有重要意义。
The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period - a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations. Most organisms have evolved an internal clock which allows them to anticipate and react to the light/dark daily rhythm and is able to generate oscillation with a circa 24 hour rhythm. A molecular network involving feedback loops is responsible for the rhythm generation. A large number of clock-controlled genes pass on time messages and control several biological processes. In spite of its medical importance (role in cancer, sleep disorders, diabetes and others) the mechanism of action of the circadian clock and the role of its constituent's feedback loops remains partially unknown. Using a mathematical model, we were able to bring insight in open circadian biology questions. Firstly, increasing the mRNA degradation rate of Per can contribute to increase or decrease of the period which might explain contradictory experimental findings. Secondly, our data points to a more relevant role of the ROR/Bmal/REV-ERB loop. In particular, that this loop can be an oscillator on its own. We provide experimental evidence that overexpression of members of the ROR/Bmal/REV-ERB lead to loss of Bmal reporter mRNA oscillations. The fact that REV-ERB and ROR are nuclear receptors and therefore important regulators in many cellular processes might have important implications for molecular biology and medicine.
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影响因子：
4.3
作者：
Bernard S;Cajavec Bernard B;Lévi F;Herzel H
通讯作者：
Herzel H
DOI：
10.1073/pnas.0707772105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Brown, Steven A.;Kunz, Dieter;Kramer, Achim
通讯作者：
Kramer, Achim
DOI：
10.1073/pnas.0604511103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Gallego, Monica;Eide, Erik J.;Forger, Daniel B.
通讯作者：
Forger, Daniel B.
影响因子：
3.4
作者：
Gonze, D;Bernard, S;Herzel, H
通讯作者：
Herzel, H
影响因子：
56.9
作者：
Glossop, NRJ;Lyons, LC;Hardin, PE
通讯作者：
Hardin, PE