Gatfield David, Le Martelot Gwendal, Vejnar Charles E, Gerlach Daniel, Schaad Olivier, Fleury-Olela Fabienne, Ruskeepää Anna-Liisa, Oresic Matej, Esau Christine C, Zdobnov Evgeny M, Schibler Ueli
Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland.
Genes Dev. 2009 Jun 1;23(11):1313-26. doi: 10.1101/gad.1781009.
In liver, most metabolic pathways are under circadian control, and hundreds of protein-encoding genes are thus transcribed in a cyclic fashion. Here we show that rhythmic transcription extends to the locus specifying miR-122, a highly abundant, hepatocyte-specific microRNA. Genetic loss-of-function and gain-of-function experiments have identified the orphan nuclear receptor REV-ERBalpha as the major circadian regulator of mir-122 transcription. Although due to its long half-life mature miR-122 accumulates at nearly constant rates throughout the day, this miRNA is tightly associated with control mechanisms governing circadian gene expression. Thus, the knockdown of miR-122 expression via an antisense oligonucleotide (ASO) strategy resulted in the up- and down-regulation of hundreds of mRNAs, of which a disproportionately high fraction accumulates in a circadian fashion. miR-122 has previously been linked to the regulation of cholesterol and lipid metabolism. The transcripts associated with these pathways indeed show the strongest time point-specific changes upon miR-122 depletion. The identification of Pparbeta/delta and the peroxisome proliferator-activated receptor alpha (PPARalpha) coactivator Smarcd1/Baf60a as novel miR-122 targets suggests an involvement of the circadian metabolic regulators of the PPAR family in miR-122-mediated metabolic control.
在肝脏中，大多数代谢途径受昼夜节律控制，因此数百个蛋白质编码基因以循环方式转录。在此我们表明，节律性转录延伸至指定miR-122的基因座，miR-122是一种高度丰富的、肝细胞特异性的微小RNA。基因功能丧失和功能获得实验已确定孤儿核受体REV-ERBα是mir-122转录的主要昼夜节律调节因子。尽管由于其较长的半衰期，成熟的miR-122在一天中以几乎恒定的速率积累，但这种微小RNA与控制昼夜节律基因表达的机制紧密相关。因此，通过反义寡核苷酸（ASO）策略敲低miR-122的表达导致数百种mRNA的上调和下调，其中不成比例的高比例以昼夜节律方式积累。miR-122先前已与胆固醇和脂质代谢的调节相关联。与这些途径相关的转录本在miR-122耗竭后确实显示出最强的时间点特异性变化。将Pparbeta/delta和过氧化物酶体增殖物激活受体α（PPARα）共激活因子Smarcd1/Baf60a鉴定为新的miR-122靶标，表明PPAR家族的昼夜节律代谢调节因子参与了miR-122介导的代谢控制。
