The interplay of cis-regulatory elements rules circadian rhythms in mouse liver.
The interplay of cis-regulatory elements rules circadian rhythms in mouse liver.
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DOI：
10.1371/journal.pone.0046835
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Herzel H
中科院分区：
文献类型：
--
作者：
Korenčič A;Bordyugov G;Košir R;Rozman D;Goličnik M;Herzel H
哺乳动物的生物钟由涉及 E 盒、D 盒和 ROR 元件的细胞自主转录反馈环路驱动。在外周器官中，昼夜节律还受到全身因素的影响。我们证明内在的组合基因调控控制着肝脏时钟。我们以 2 小时的时间分辨率，测量了持续黑暗和春分明暗循环下小鼠肝脏中 21 个时钟基因的表达。基于这些数据和已知的转录因子结合位点，我们开发了一个六变量基因调控网络。转录反馈环由具有时滞变量的方程表示，这大大简化了中间蛋白质动力学的建模。我们的模型准确地再现了时钟基因的测量相位、幅度和波形。对网络的分析揭示了时钟的特性：过临界的延迟会产生振荡；抑制和激活的协同作用增强振幅；转录的组合调节控制阶段。测量和模拟的一致性表明，内在基因调控网络主要决定肝脏的生物钟，而诸如明暗周期之类的系统线索则用于微调节律。
The mammalian circadian clock is driven by cell-autonomous transcriptional feedback loops that involve E-boxes, D-boxes, and ROR-elements. In peripheral organs, circadian rhythms are additionally affected by systemic factors. We show that intrinsic combinatorial gene regulation governs the liver clock. With a temporal resolution of 2 h, we measured the expression of 21 clock genes in mouse liver under constant darkness and equinoctial light-dark cycles. Based on these data and known transcription factor binding sites, we develop a six-variable gene regulatory network. The transcriptional feedback loops are represented by equations with time-delayed variables, which substantially simplifies modelling of intermediate protein dynamics. Our model accurately reproduces measured phases, amplitudes, and waveforms of clock genes. Analysis of the network reveals properties of the clock: overcritical delays generate oscillations; synergy of inhibition and activation enhances amplitudes; and combinatorial modulation of transcription controls the phases. The agreement of measurements and simulations suggests that the intrinsic gene regulatory network primarily determines the circadian clock in liver, whereas systemic cues such as light-dark cycles serve to fine-tune the rhythms.
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影响因子：
4.5
作者：
Liu AC;Tran HG;Zhang EE;Priest AA;Welsh DK;Kay SA
通讯作者：
Kay SA
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：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
GLASS, L
DOI：
10.1073/pnas.1107178108
发表时间：
2011-09-27
影响因子：
11.1
作者：
Lee, Hyeong-Min;Chen, Rongmin;Lee, Choogon
通讯作者：
Lee, Choogon