Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator.
Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator.
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DOI：
10.1371/journal.pcbi.1005266
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发表时间：
2016-12
影响因子：
4.3
通讯作者：
Herzel H
中科院分区：
文献类型：
--
作者：
Pett JP;Korenčič A;Wesener F;Kramer A;Herzel H
哺乳动物进化出一种内源性的计时系统，以协调它们的生理和行为与太阳日的24小时周期。虽然人们普遍认为昼夜节律是由细胞内转录反馈环产生的，但仍有争议，哪些网络基序是产生自我维持振荡的必要条件和充分条件。在这里，我们系统地探索了一个具有多个负反馈环和正反馈环的基于数据的昼夜节律振荡器模型，并发现一系列被称为“抑制物”的三种后续抑制是哺乳动物昼夜节律振荡器的核心元件。抑制基序的中心作用与生物钟转录因子的时间分辨芯片序列实验和核心时钟基因敲除的节律性丧失是一致的。生物钟是内源振荡器，驱动生理、新陈代谢和行为的日常节奏。近年来，我们在了解这些时钟的机制和遗传基础方面取得了巨大的进步。虽然数学模型对我们目前对生物钟网络的看法做出了重要贡献，但仍然存在争议，即哪些网络基元是产生自持续振荡的必要条件和充分条件。利用数据驱动的数学模型，我们在这里将“抑制器”确定为关键的设计原则。抑制基序的中心作用与生物钟转录因子的时间分辨结合数据和核心时钟基因敲除中的节律性丧失是一致的。
Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts. Circadian clocks are endogenous oscillators that drive daily rhythms in physiology, metabolism and behavior. The recent years have witnessed enormous progress in our understanding of the mechanistic and genetic basis of these clocks. While mathematical modelling has made important contributions to our current view of the circadian clock network, it is still debated, which network motifs are necessary and sufficient for generating self-sustained oscillations. Exploiting a data-driven mathematical model we here identify the “repressilator” as a key design principal. The central role of the repressilator motif is consistent with time-resolved binding data of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts.
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影响因子：
4.6
作者：
Korencic, Anja;Kosir, Rok;Herzel, Hanspeter
通讯作者：
Herzel, Hanspeter
影响因子：
9.2
作者：
de la Iglesia, HO;Cambras, T;Díez-Noguera, A
通讯作者：
Díez-Noguera, A
影响因子：
3.4
作者：
Gonze, D;Bernard, S;Herzel, H
通讯作者：
Herzel, H
影响因子：
3.7
作者：
Korenčič A;Bordyugov G;Košir R;Rozman D;Goličnik M;Herzel H
通讯作者：
Herzel H
影响因子：
9.9
作者：
Kim, Jae Kyoung;Forger, Daniel B.
通讯作者：
Forger, Daniel B.