Rhythmic histone acetylation underlies transcription in the mammalian circadian clock
Rhythmic histone acetylation underlies transcription in the mammalian circadian clock
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DOI：
10.1038/nature01314
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发表时间：
2003-01-09
期刊：
影响因子：
64.8
通讯作者：
Reppert, SM
中科院分区：
文献类型：
--
作者：
Etchegaray, JP;Lee, C;Reppert, SM
在小鼠生物钟中，转录反馈环路位于发条机制的中心。 Clock 和 Bmal1 是驱动三个周期基因 (Per1-3) 和两个隐花色素基因（Cry1 和 Cry2）(1-5) 表达的重要转录因子。 Cry 蛋白通过不改变 Clock/Bmal1 与 DNA 结合的机制进行反馈，抑制 Clock/Bmal1 介导的转录(6)。在这里，我们发现小鼠肝脏核心时钟机制的转录调控伴随着 H3 组蛋白乙酰化的节律，并且 H3 乙酰化是 Cry 抑制作用的潜在靶点。 Per1、Per2 和 Cry1 基因的启动子区域在 H3 乙酰化和 RNA 聚合酶 II 结合方面表现出昼夜节律，与相应的稳态信使 RNA 节律同步。组蛋白乙酰转移酶 p300 在体内以时间依赖性方式与 Clock 一起沉淀。此外，Cry 蛋白抑制 p300 诱导的 Clock/Bmal1 介导的转录增加。相对于 Per 节律，Cry1 mRNA 节律的延迟时间是由于 Rev-Erbalpha 和 Clock/Bmal1 的协调活动所致，并定义了昼夜节律相位控制的新机制。
In the mouse circadian clock, a transcriptional feedback loop is at the centre of the clockwork mechanism. Clock and Bmal1 are essential transcription factors that drive the expression of three period genes (Per1-3) and two cryptochrome genes (Cry1 and Cry2)(1-5). The Cry proteins feedback to inhibit Clock/Bmal1-mediated transcription by a mechanism that does not alter Clock/Bmal1 binding to DNA(6). Here we show that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1, Per2 and Cry1 genes exhibit circadian rhythms in H3 acetylation and RNA polymerase II binding that are synchronous with the corresponding steady-state messenger RNA rhythms. The histone acetyltransferase p300 precipitates together with Clock in vivo in a time-dependent manner. Moreover, the Cry proteins inhibit a p300-induced increase in Clock/Bmal1-mediated transcription. The delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, is due to the coordinated activities of Rev-Erbalpha and Clock/Bmal1, and defines a new mechanism for circadian phase control.