Delay in Feedback Repression by Cryptochrome 1 Is Required for Circadian Clock Function
Delay in Feedback Repression by Cryptochrome 1 Is Required for Circadian Clock Function
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DOI：
10.1016/j.cell.2010.12.019
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发表时间：
2011-01-21
期刊：
影响因子：
64.5
通讯作者：
Ueda, Hiroki R.
中科院分区：
文献类型：
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作者：
Ukai-Tadenuma, Maki;Yamada, Rikuhiro G.;Ueda, Hiroki R.
哺乳动物生物钟中反馈抑制需要延迟的直接证据一直难以捉摸。隐花色素1（Cry 1），一个重要的时钟组件，显示晚上的时间表达，并作为一个强阻遏物在早晨的时间元素（E框/E'框）。在这项研究中，我们发现，白天的元素（D盒）内的Cry 1近端启动子和夜间的元素（RREs）内的内含子增强子的组合引起了晚上的表达。合成的复合启动子产生晚上的时间表达，这是进一步概括了一个简单的相载体模型。值得注意的是，白天与夜间元素的协调可以调节相位延迟的程度。在Cry 1（-/-）：Cry 2（-/-）细胞中的遗传互补测定揭示了Cry 1表达的实质性延迟是恢复昼夜节律性所必需的，并且其延长的延迟减缓了昼夜节律振荡。两者合计，我们的数据表明，在Cry 1转录的相位延迟所需的哺乳动物的时钟功能。
Direct evidence for the requirement of delay in feedback repression in the mammalian circadian clock has been elusive. Cryptochrome 1 (Cry1), an essential clock component, displays evening-time expression and serves as a strong repressor at morning-time elements (E box/E' box). In this study, we reveal that a combination of day-time elements (D box) within the Cry1-proximal promoter and night-time elements (RREs) within its intronic enhancer gives rise to evening-time expression. A synthetic composite promoter produced evening-time expression, which was further recapitulated by a simple phase-vector model. Of note, coordination of day-time with night-time elements can modulate the extent of phase delay. A genetic complementation assay in Cry1(-/-):Cry2(-/-) cells revealed that substantial delay of Cry1 expression is required to restore circadian rhythmicity, and its prolonged delay slows circadian oscillation. Taken together, our data suggest that phase delay in Cry1 transcription is required for mammalian clock function.