miRNAs are required for generating a time delay critical for the circadian oscillator.
miRNAs are required for generating a time delay critical for the circadian oscillator.
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DOI：
10.1016/j.cub.2013.08.005
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发表时间：
2013-10-21
期刊：
影响因子：
--
通讯作者：
Lee C
中科院分区：
文献类型：
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作者：
Chen R;D'Alessandro M;Lee C
昼夜节律时钟协调生物体的活动并调节与日常环境变化（最明显的是光/暗周期）相关的代谢稳态。与其他生物体一样，哺乳动物的计时机制依赖于自我维持的转录负反馈环路，具有内置的反馈抑制时间延迟。尽管时间延迟对于生成周期接近 24 小时的缓慢、自我维持的负反馈循环至关重要，但时间延迟背后的确切机制尚不清楚。我们在此表明，由 microRNA (miRNA) 介导的 RNA 干扰是产生时间延迟的重要机制。在 Dicer 缺陷（因此 miRNA 缺陷）的细胞和小鼠中，昼夜节律显着缩短（约 2 小时），尽管节律仍然保持稳健。周期缩短是由于 Dicer 缺陷细胞中 PER1 和 PER2 翻译速度加快所致。我们还鉴定了三种调节 Per 表达的特定 miRNA，并表明在野生型细胞中敲低这些 miRNA 也会缩短昼夜节律。与 miRNA 作为靶基因翻译调节剂的典型功能及其在细胞生理学中的广泛作用一致，昼夜节律也受到 miRNA 介导的 RNA 干扰的调节，RNA 干扰作用于关键时钟基因的转录后调节。我们目前的研究明确表明，RNA 干扰通过控制 PER 合成的速度，成为昼夜节律的重要调节剂，并为生物钟提供了一种新的调节层。
Circadian clocks coordinate an organism’s activities and regulate metabolic homeostasis in relation to daily environmental changes, most notably light/dark cycles. As in other organisms, the timekeeping mechanism in mammals depends on a self-sustaining transcriptional negative feedback loop with a built-in time delay in feedback inhibition. Although the time delay is essential for generating a slow, self-sustaining negative feedback loop with a period close to 24 hours, the exact mechanisms underlying the time delay are not known. We show here that RNA interference mediated by microRNAs (miRNAs) is an essential mechanism in generating the time delay. In Dicer-deficient (and thus miRNA-deficient) cells and mice, circadian rhythms were dramatically shortened (by ~2 hours), although the rhythms remained robust. The period shortening was caused by faster PER1 and PER2 translation in the Dicer-deficient cells. We also identified three specific miRNAs that regulate Per expression, and showed that knockdown of these miRNAs in wild-type cells also shortened the circadian period. Consistent with the canonical function of miRNAs as translational modulators of target genes and their widespread roles in cell physiology, circadian rhythms are also modulated by miRNA-mediated RNA interference acting on posttranscriptional regulation of key clock genes. Our present study definitively shows that RNA interference is an important modulator of circadian rhythms by controlling the pace of PER synthesis, and presents a novel layer of regulation for the clock.