RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock
RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock
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DOI：
10.1016/j.cell.2013.10.026
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发表时间：
2013-11-07
期刊：
影响因子：
64.5
通讯作者：
Okamura, Hitoshi
中科院分区：
文献类型：
--
作者：
Fustin, Jean-Michel;Doi, Masao;Okamura, Hitoshi
真核生物的生物钟是一个负转录-翻译反馈环，生物钟基因在这个反馈环中调节自身的转录和代谢产物基因的转录。虽然大约10%的肝脏转录组是有节奏的，但只有大约五分之一是由从头转录驱动的，这表明mRNA加工是主要的昼夜节律组成部分。在这里，我们报告说，抑制甲基转移反应延长昼夜节律周期。然后RNA测序揭示甲基化抑制导致RNA加工机制的转录发生广泛变化，与m（6）A-RNA甲基化相关。我们鉴定了许多时钟基因转录本上的m（6）A位点，并表明通过沉默m（6）A甲基化酶Mettl 3来特异性抑制m（6）A甲基化足以引起昼夜节律周期延长和RNA加工延迟。时钟基因Per 2和Arntl的昼夜节律核质分布的分析揭示了当m（6）A甲基化被抑制时，稳态前mRNA和细胞质mRNA节律之间的解偶联。
The eukaryotic biological clock involves a negative transcription-translation feedback loop in which clock genes regulate their own transcription and that of output genes of metabolic significance. While around 10% of the liver transcriptome is rhythmic, only about a fifth is driven by de novo transcription, indicating mRNA processing is a major circadian component. Here, we report that inhibition of transmethylation reactions elongates the circadian period. RNA sequencing then reveals methylation inhibition causes widespread changes in the transcription of the RNA processing machinery, associated with m(6)A-RNA methylation. We identify m(6)A sites on many clock gene transcripts and show that specific inhibition of m(6)A methylation by silencing of the m(6)A methylase Mettl3 is sufficient to elicit circadian period elongation and RNA processing delay. Analysis of the circadian nucleocytoplasmic distribution of clock genes Per2 and Arntl then revealed an uncoupling between steady-state pre-mRNA and cytoplasmic mRNA rhythms when m(6)A methylation is inhibited.