Post-transcriptional control of circadian rhythms

Department of Neuroscience, University of Texas Southwestern Medical Center, NB4.204G, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Journal of Cell Science (Impact Factor: 5.43). 02/2011; 124(Pt 3):311-20. DOI: 10.1242/jcs.065771
Source: PubMed


Circadian rhythms exist in most living organisms. The general molecular mechanisms that are used to generate 24-hour rhythms are conserved among organisms, although the details vary. These core clocks consist of multiple regulatory feedback loops, and must be coordinated and orchestrated appropriately for the fine-tuning of the 24-hour period. Many levels of regulation are important for the proper functioning of the circadian clock, including transcriptional, post-transcriptional and post-translational mechanisms. In recent years, new information about post-transcriptional regulation in the circadian system has been discovered. Such regulation has been shown to alter the phase and amplitude of rhythmic mRNA and protein expression in many organisms. Therefore, this Commentary will provide an overview of current knowledge of post-transcriptional regulation of the clock genes and clock-controlled genes in dinoflagellates, plants, fungi and animals. This article will also highlight how circadian gene expression is modulated by post-transcriptional mechanisms and how this is crucial for robust circadian rhythmicity.

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Available from: Shihoko Kojima, Oct 06, 2015
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    • "The expression of most genes is regulated temporally and spatially. Although most of the regulation of gene expression occurs at the transcription step, the regulation of mRNA stability, localization and modulation of translation are crucial steps, particularly in developmental processes (1) and biological clock systems (2–5). Expression profiles of mRNA or protein are not matched in many cases, implying that translational control is a dynamically regulated mechanism, which is not a silent step (6–8). "
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    ABSTRACT: In the present study, we investigated the 3' untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3'UTR is widely known to function as a cis-acting element of mRNA degradation. The 3'UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3'UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3'UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3'UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3'UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3'UTR facilitates interaction with the 5' end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.
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    • "The circadian clock was initially modeled as interlocked transcription–translation feedback loops that drive rhythms in gene expression of core CLOCK, BMAL, PER, and CRY genes[1,3]. In addition to these classic feedback loops, circadian regulation has been demonstrated to involve posttranscriptional, translational, and posttranslational mechanisms[4,5]. Importantly microRNAs (miRNAs) and double stranded RNA (dsRNA) were shown to play a vital role in regulating various aspects of circadian clock function[4,6]. "
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    ABSTRACT: Dysregulation of circadian rhythmicity is identified as a key factor in disease pathogenesis. Circadian rhythmicity is controlled at both a transcriptional and post-transcriptional level suggesting the role of microRNA (miRNA) and double-stranded RNA (dsRNA) in this process. Endonuclease Dicer controls miRNA and dsRNA processing, however the role of Dicer in circadian regulation is not known. Here we demonstrate robust diurnal oscillations of Dicer expression in central and peripheral clock control systems including suprachiasmatic nucleolus (SCN), retina, liver, and bone marrow (BM). The Dicer oscillations were either reduced or phase shifted with aging and Type 2 diabetes. The decrease and phase shift of Dicer expression was associated with a similar decrease and phase shift of miRNAs 146a and 125a-5p and with an increase in toxic Alu RNA. Restoring Dicer levels and the diurnal patterns of Dicer-controlled miRNA and RNA expression may provide new therapeutic strategies for metabolic disease and aging-associated complications.
    PLoS ONE 11/2013; 8(11):e80029. DOI:10.1371/journal.pone.0080029 · 3.23 Impact Factor
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    • "When considering the therapeutic potential of miRNAs, it must be kept in mind that by aiming at several targets, some displaying antagonizing effects, miRNAs could exert dual actions. In the context of the miRNA-metabolism crosstalk, an igniting question relates to the impact of circadian rhythms (Kojima et al., 2011). This aspect is particularly relevant considering the fact that feeding (i.e., nutrients) modulates the circadian clock and that the latter regulates metabolism. "
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    ABSTRACT: In record time, microRNAs (miRNAs) have acquired the respected stature of important natural regulators of global gene expression. Multiple studies have demonstrated that a large number of miRNAs are under the control of various metabolic stimuli, including nutrients, hormones, and cytokines. Conversely, it is now well recognized that miRNAs control metabolism, thereby generating a bidirectional functional link, which perturbs energy homeostasis in case of disconnection in the miRNA-metabolism interplay. A challenging road lies ahead for defining the role of miRNAs in the pathogenesis of diseases such as diabetes and for establishing their usefulness as new medications and clinically reliable biomarkers.
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