Positive autoregulation delays the expression phase of mammalian clock gene Per2.
Positive autoregulation delays the expression phase of mammalian clock gene Per2.
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DOI：
10.1371/journal.pone.0018663
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发表时间：
2011-04-14
期刊：
影响因子：
3.7
通讯作者：
Tei H
中科院分区：
文献类型：
--
作者：
Ogawa Y;Koike N;Kurosawa G;Soga T;Tomita M;Tei H
在哺乳动物中，细胞昼夜节律是由转录-翻译自调节网络产生的，该网络由编码转录调节因子的时钟基因组成。在这些生物钟基因中，周期1 （Per1）和周期2 （Per2）对于持续的昼夜节律和光诱导至关重要。有趣的是，Per1和Per2 mrna表现出具有4小时相位差异的昼夜振荡，但它们同样被CLOCK-BMAL1反激活。在本研究中，我们通过数学模拟和分子实验相结合的方法研究了Per1和Per2之间相位差的机制。对哺乳动物昼夜节律振荡器模型的数学分析表明，mRNA的缓慢合成和快速降解倾向于提前mRNA表达的振荡阶段。然而，该模型无法再现Per1和Per2之间的相位差，在培养的哺乳动物细胞中，该模型实现了降解率的1.1倍差异和CLOCK-BMAL1介导的Per1和Per2诱导的3倍差异。因此，我们假设存在PER1/2对Per2的一种新的转录激活，使得Per2的振荡期被延迟。事实上，在荧光素酶报告基因实验中，在CLOCK-BMAL1存在的情况下，只有Per2启动子被Per1和Per2强烈诱导，而不是Per1。此外，缺乏PER1/2诱导所需的顺式元件的delta-Per2报告基因的转录振荡提前了3小时。这些结果表明，Per2正反馈调控是造成Per1和Per2基因表达相位差的重要因素。
In mammals, cellular circadian rhythms are generated by a transcriptional-translational autoregulatory network that consists of clock genes that encode transcriptional regulators. Of these clock genes, Period1 (Per1) and Period2 (Per2) are essential for sustainable circadian rhythmicity and photic entrainment. Intriguingly, Per1 and Per2 mRNAs exhibit circadian oscillations with a 4-hour phase difference, but they are similarly transactivated by CLOCK-BMAL1. In this study, we investigated the mechanism underlying the phase difference between Per1 and Per2 through a combination of mathematical simulations and molecular experiments. Mathematical analyses of a model for the mammalian circadian oscillator demonstrated that the slow synthesis and fast degradation of mRNA tend to advance the oscillation phase of mRNA expression. However, the phase difference between Per1 and Per2 was not reproduced by the model, which implemented a 1.1-fold difference in degradation rates and a 3-fold difference in CLOCK-BMAL1 mediated inductions of Per1 and Per2 as estimated in cultured mammalian cells. Thus, we hypothesized the existence of a novel transcriptional activation of Per2 by PER1/2 such that the Per2 oscillation phase was delayed. Indeed, only the Per2 promoter, but not Per1, was strongly induced by both PER1 and PER2 in the presence of CLOCK-BMAL1 in a luciferase reporter assay. Moreover, a 3-hour advance was observed in the transcriptional oscillation of the delta-Per2 reporter gene lacking cis-elements required for the induction by PER1/2. These results indicate that the Per2 positive feedback regulation is a significant factor responsible for generating the phase difference between Per1 and Per2 gene expression.
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影响因子：
16.2
作者：
Shearman, LP;Zylka, MJ;Reppert, SM
通讯作者：
Reppert, SM
影响因子：
9.2
作者：
Akhtar, RA;Reddy, AB;Kyriacou, CP
通讯作者：
Kyriacou, CP
影响因子：
64.5
作者：
GLUZMAN, Y
通讯作者：
GLUZMAN, Y
影响因子：
4.3
作者：
Hornung G;Barkai N
通讯作者：
Barkai N
DOI：
10.1073/pnas.0904837106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Mirsky, Henry P.;Liu, Andrew C.;Doyle, Francis J., III
通讯作者：
Doyle, Francis J., III