Dataset Information

Two Ck1? transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

ABSTRACT: The N6-methylation of internal adenosines (m6A) in mRNA has been quantified and localized throughout the transcriptome. However, the physiological significance of m6A in most highly methylated mRNAs is unknown. It was demonstrated previously that the circadian clock, based on transcription-translation negative feedback loops, is sensitive to the general inhibition of m6A. Here, we show that the Casein Kinase 1 Delta mRNA (Ck1?), coding for a critical kinase in the control of circadian rhythms, cellular growth, and survival, is negatively regulated by m6A. Inhibition of Ck1? mRNA methylation leads to increased translation of two alternatively spliced CK1? isoforms, CK1?1 and CK1?2, uncharacterized until now. The expression ratio between these isoforms is tissue-specific, CK1?1 and CK1?2 have different kinase activities, and they cooperate in the phosphorylation of the circadian clock protein PER2. While CK1?1 accelerates the circadian clock by promoting the decay of PER2 proteins, CK1?2 slows it down by stabilizing PER2 via increased phosphorylation at a key residue on PER2 protein. These observations challenge the previously established model of PER2 phosphorylation and, given the multiple functions and targets of CK1?, the existence of two isoforms calls for a re-evaluation of past research when CK1?1 and CK1?2 were simply CK1?.

SUBMITTER: Fustin JM

PROVIDER: S-EPMC6003373 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

Fustin Jean-Michel JM Kojima Rika R Itoh Kakeru K Chang Hsin-Yi HY Ye Shiqi S Zhuang Bowen B Oji Asami A Gibo Shingo S Narasimamurthy Rajesh R Virshup David D Kurosawa Gen G Doi Masao M Manabe Ichiro I Ishihama Yasushi Y Ikawa Masahito M Okamura Hitoshi H

Proceedings of the National Academy of Sciences of the United States of America 20180521 23

The N6-methylation of internal adenosines (m6A) in mRNA has been quantified and localized throughout the transcriptome. However, the physiological significance of m6A in most highly methylated mRNAs is unknown. It was demonstrated previously that the circadian clock, based on transcription-translation negative feedback loops, is sensitive to the general inhibition of m6A. Here, we show that the Casein Kinase 1 Delta mRNA (Ck1δ), coding for a critical kinase in the contro ...[more]

PMID: 29784786

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Project description:In recent years, it has become increasingly apparent that antisense transcription plays an important role in the regulation of gene expression. The circadian clock is no exception: an antisense transcript of the mammalian core-clock gene PERIOD2 (PER2), which we shall refer to as Per2AS RNA, oscillates with a circadian period and a nearly 12 h phase shift from the peak expression of Per2 mRNA. In this paper, we ask whether Per2AS plays a regulatory role in the mammalian circadian clock by studying in silico the potential effects of interactions between Per2 and Per2AS RNAs on circadian rhythms. Based on the antiphasic expression pattern, we consider two hypotheses about how Per2 and Per2AS mutually interfere with each other's expression. In our pre-transcriptional model, the transcription of Per2AS RNA from the non-coding strand represses the transcription of Per2 mRNA from the coding strand and vice versa. In our post-transcriptional model, Per2 and Per2AS transcripts form a double-stranded RNA duplex, which is rapidly degraded. To study these two possible mechanisms, we have added terms describing our alternative hypotheses to a published mathematical model of the molecular regulatory network of the mammalian circadian clock. Our pre-transcriptional model predicts that transcriptional interference between Per2 and Per2AS can generate alternative modes of circadian oscillations, which we characterize in terms of the amplitude and phase of oscillation of core clock genes. In our post-transcriptional model, Per2/Per2AS duplex formation dampens the circadian rhythm. In a model that combines pre- and post-transcriptional controls, the period, amplitude and phase of circadian proteins exhibit non-monotonic dependencies on the rate of expression of Per2AS. All three models provide potential explanations of the observed antiphasic, circadian oscillations of Per2 and Per2AS RNAs. They make discordant predictions that can be tested experimentally in order to distinguish among these alternative hypotheses.

Project description:The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period--a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations.

Dataset Information

Two Ck1? transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

Publications

Two <i>Ck1δ</i> transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

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