Dicer Expression Exhibits a Tissue-Specific Diurnal Pattern That Is Lost during Aging and in Diabetes

Yuanqing Yan,Ashay D Bhatwadekar,Dung V Nguyen,Xiaoping Qi,James M Dominguez,Sergio Li Calzi,Michael E Boulton,Tatiana E Salazar,Julia V Busik,Maria B Grant

doi:10.1371/journal.pone.0080029

Yuanqing Yan, Ashay D Bhatwadekar + Show 8 more

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https://doi.org/10.1371/journal.pone.0080029

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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.

Highlights

Most human physiological and behavioral activities, as well as cellular and metabolic functions, are under strong circadian regulation, including rest-activity cycles, body temperature rhythms, hormone secretion, and gene expression patterns[1]
To evaluate whether Dicer exhibited a similar diurnal tissue-specific pattern, the levels of Dicer mRNA were examined in the suprachiasmatic nucleolus (SCN), liver, retina, and bone marrow mononuclear cells (BMNC) from young mice
In the SCN and BMNC, peak expression was observed at Zeitgeber Time (ZT) 5

Summary

Introduction

Most human physiological and behavioral activities, as well as cellular and metabolic functions, are under strong circadian regulation, including rest-activity cycles, body temperature rhythms, hormone secretion, and gene expression patterns[1]. 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]. MicroRNAs (miRNAs) and double stranded RNA (dsRNA) were shown to play a vital role in regulating various aspects of circadian clock function[4,6]. Degradation of circadian clock genes, which play an integral role in clock regulation, is controlled in part by miRNA[7]

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