title: RNA-methylation-dependent RNA processing controls the speed of the circadian clock.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Department of System Biology, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Fustin
authors.forename: Masao
authors.initials: M
authors.lastname: Doi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Hayashi
authors.initials: H
authors.lastname: Hida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.forename: Masaki Suimye
authors.initials: MS
authors.lastname: Morioka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamura
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D055785:Gene Knockdown Techniques; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D014372:Tubercidin / Q000494:pharmacology
chemical_list: C497396:ARNT protein, human; C421902:PER2 protein, human; D056950:Period Circadian Proteins; C018258:3-deazaadenosine; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D012313:RNA; D008780:Methyltransferases; C468275:METTL3 protein, human; D014372:Tubercidin