Atger Florian, Gobet Cédric, Marquis Julien, Martin Eva, Wang Jingkui, Weger Benjamin, Lefebvre Grégory, Descombes Patrick, Naef Felix, Gachon Frédéric
Department of Diabetes and Circadian Rhythms, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland; Department of Pharmacology and Toxicology, University of Lausanne, CH-1011 Lausanne, Switzerland;
Department of Diabetes and Circadian Rhythms, Nestlé Institute of Health Sciences, CH-1015 Lausanne, Switzerland; Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland;
Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6579-88. doi: 10.1073/pnas.1515308112. Epub 2015 Nov 9.
Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.
基因表达的昼夜振荡是大多数生物节律生理学的一个标志。这种振荡受生物钟和进食节律之间相互作用的控制。尽管节律性mRNA积累已得到广泛研究,但对其转录和翻译的了解相对较少。在这里,我们在生理明暗条件下以及野生型和脑与肌肉芳香烃受体核转运蛋白样蛋白1(Bmal1)缺陷动物自由进食或夜间限制进食的情况下,同时对小鼠肝脏mRNA的时间转录、积累和翻译进行了定量分析。我们发现,对于大多数基因而言,节律性转录主要驱动节律性mRNA积累和翻译。野生型和Bmal1基因敲除小鼠的比较表明,生物钟和进食节律对节律性基因表达有广泛影响,Bmal1缺失对转录水平和转录后水平均有惊人影响。对于具有5'-末端寡嘧啶序列(5'-TOP)的基因以及参与线粒体活性的基因(其中许多含有短5'-非翻译区翻译起始子(TISU)基序),翻译效率在昼夜周期中受到不同调节。5'-TOP和TISU基因翻译效率的提高主要由进食节律驱动,但Bmal1缺失也会影响翻译的幅度和相位,包括TISU基因。这项研究共同强调了昼夜节律和进食节律在多个步骤之间的复杂相互联系,这些步骤最终决定了节律性基因表达和翻译。