MicroRNA-122 modulates the rhythmic expression profile of the circadian deadenylase Nocturnin in mouse liver.
MicroRNA-122 modulates the rhythmic expression profile of the circadian deadenylase Nocturnin in mouse liver.
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DOI：
10.1371/journal.pone.0011264
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发表时间：
2010-06-22
期刊：
影响因子：
3.7
通讯作者：
Green CB
中科院分区：
文献类型：
--
作者：
Kojima S;Gatfield D;Esau CC;Green CB
Nocturnin是一种生物钟调节的去腺苷酶，被认为通过去除poly（A）尾来控制转录后mRNA的表达。在mRNA和蛋白质水平上，Nocturnin在肝脏中的表达具有强烈的节律性，缺乏Nocturnin的小鼠对饮食诱导的肥胖和肝脏脂肪变性具有抵抗力。在这里，我们报告Nocturnin的表达是由microRNA-122（miR-122），肝脏特异性的miRNA。我们发现Nocturnin mRNA的3 '-非翻译区（3'-UTR）含有一个推定的miR-122识别位点，并且该位点在哺乳动物中是保守的。使用野生型或突变型Nocturnin 3′-UTR序列的荧光素酶报告基因构建体，我们证明了miR-122的过表达可以下调荧光素酶活性水平，并且这种作用依赖于推定的miR-122识别位点的存在。此外，使用反义寡核苷酸在体内敲低miR-122导致夜间小鼠肝脏中Nocturnin mRNA和蛋白质表达的显著上调，从而导致幅度增加的Nocturnin节律。总之，这些数据表明，肝脏中Nocturnin表达的正常节律分布部分由miR-122形成。以前的研究表明，Nocturnin和miR-122是肝脏中脂质代谢和生物钟控制基因表达的重要转录后调节因子。因此，证明miR-122在调节Nocturnin表达中起作用表明这可能是肝脏代谢和昼夜节律控制之间的重要交叉点。
Nocturnin is a circadian clock-regulated deadenylase thought to control mRNA expression post-transcriptionally through poly(A) tail removal. The expression of Nocturnin is robustly rhythmic in liver at both the mRNA and protein levels, and mice lacking Nocturnin are resistant to diet-induced obesity and hepatic steatosis. Here we report that Nocturnin expression is regulated by microRNA-122 (miR-122), a liver specific miRNA. We found that the 3′-untranslated region (3′-UTR) of Nocturnin mRNA harbors one putative recognition site for miR-122, and this site is conserved among mammals. Using a luciferase reporter construct with wild-type or mutant Nocturnin 3′-UTR sequence, we demonstrated that overexpression of miR-122 can down-regulate luciferase activity levels and that this effect is dependent on the presence of the putative miR-122 recognition site. Additionally, the use of an antisense oligonucleotide to knock down miR-122 in vivo resulted in significant up-regulation of both Nocturnin mRNA and protein expression in mouse liver during the night, resulting in Nocturnin rhythms with increased amplitude. Together, these data demonstrate that the normal rhythmic profile of Nocturnin expression in liver is shaped in part by miR-122. Previous studies have implicated Nocturnin and miR-122 as important post-transcriptional regulators of both lipid metabolism and circadian clock controlled gene expression in the liver. Therefore, the demonstration that miR-122 plays a role in regulating Nocturnin expression suggests that this may be an important intersection between hepatic metabolic and circadian control.
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