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,
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    • "Daily changes in RNA stability , for instance, could account for such rhythms in a way that even though the gene may be transcribed uniformly throughout the day, the stability of the resulting mRNA would change daily and would be detected as a cycling mRNA. This could be mediated, for instance, by specific proteins/noncoding RNAs (ncRNAs) that interact with the target mRNAs and mediate its rhythmic decay (for examples, see Kojima et al., 2011 "
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    ABSTRACT: Circadian clocks drive daily oscillations in a variety of biological processes through the coordinate orchestration of precise gene expression programs. Global expression profiling experiments have suggested that a significant fraction of the transcriptome and proteome is under circadian control, and such output rhythms have historically been assumed to rely on the rhythmic transcription of these genes. Recent genome-wide studies, however, have challenged this long-held view and pointed to a major contribution of posttranscriptional regulation in driving oscillations at the messenger RNA (mRNA) level, while others have highlighted extensive clock translational regulation, regardless of mRNA rhythms. There are various examples of genes that are uniformly transcribed throughout the day but that exhibit rhythmic mRNA levels, and of flat mRNAs, with oscillating protein levels, and such observations have largely been considered to result from independent regulation at each step. These studies have thereby obviated any connections, or coupling, that might exist between the different steps of gene expression and the impact that any of them could have on subsequent ones. Here, we argue that due to both biological and technical reasons, the jury is still out on the determination of the relative contributions of each of the different stages of gene expression in regulating output molecular rhythms. In addition, we propose that through a variety of coupling mechanisms, gene transcription (even when apparently arrhythmic) might play a much relevant role in determining oscillations in gene expression than currently estimated, regulating rhythms at downstream steps. Furthermore, we posit that eukaryotic genomes regulate daily RNA polymerase II (RNAPII) recruitment and histone modifications genome-wide, setting the stage for global nascent transcription, but that tissue-specific mechanisms locally specify the different processes under clock control.
    Journal of Biological Rhythms 10/2015; DOI:10.1177/0748730415607321 · 2.77 Impact Factor
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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.
    Nucleic Acids Research 01/2014; 42(6). DOI:10.1093/nar/gkt1379 · 9.11 Impact Factor
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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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