MicroRNAs: a potential interface between the circadian clock and human health - PubMed (original) (raw)

MicroRNAs: a potential interface between the circadian clock and human health

Katelin F Hansen et al. Genome Med. 2011.

Abstract

The biochemical activity of a stunning diversity of cell types and organ systems is shaped by a 24-hour (circadian) clock. This rhythmic drive to a good deal of the transcriptome (up to 15% of all coding genes) imparts circadian modulation over a wide range of physiological and behavioral processes (from cell division to cognition). Further, dysregulation of the clock has been implicated in the pathogenesis of a large and diverse array of disorders, such as hypertension, cancer and depression. Indeed, the possibility of utilizing therapeutic approaches that target clock physiology (that is, chronotherapy) has gained broad interest. However, a deeper understanding of the underlying molecular mechanisms that modulate the clock, and give rise to organ-specific clock transcriptomes, will be required to fully realize the power of chronotherapies. Recently, microRNAs have emerged as significant players in circadian clock timing, thus raising the possibility that clock-controlled microRNAs could contribute to disorders of the human circadian timing system. Here, we highlight recent work revealing a key role for microRNAs in clock physiology, and discuss potential approaches to unlocking their utility as effectors of circadian physiology and pathophysiology.

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Figures

Figure 1

Figure 1

Schematic overview of molecular circadian clock timing. (a) Suprachiasmatic nucleus (SCN; red circles) located within the ventral hypothalamus. The two nuclei serve as the master circadian clocks, orchestrating rhythmicity and phasing of ancillary clocks found in peripheral organ systems (c1) and throughout the brain (c2). Entrainment of the SCN clock to light is mediated by a direct projection from the retina. (b) The molecular clock feedback loop is centered on the rhythmic expression of the period (per1/2) and cryptochrome (cry1/2) gene families. PERIOD and CRY dimers translocate to the nucleus and negatively regulate their own production via suppression of CLOCK (CLK)- and BMAL1-mediated transcription. Casein kinase 1 (CK1)-mediated phosphorylation triggers degradation of PER proteins, thus relieving transcriptional repression and, in turn, allowing for robust 24-hour clock gene cycling. In addition to the core clock genes, a large fraction of the transcriptome is under the direct or indirect influence of the circadian clock. The clock-controlled transcriptome (CCT) within the SCN includes hormones, kinases, transcription factors and microRNAs. Many of these gene products serve as phasing cues to ancillary oscillators, or function as feedback regulators of the core molecular clock. (c1) Clock-regulated microRNA expression in the liver: denotation of several rhythmically expressed microRNAs that are either predicted (that is, miR181 d and miR191 [69]) or have been shown (that is, miR192/194 [71]) to target components of the core molecular clock. MiR122 has been shown to modulate clock-controlled gene expression involved in hepatic cholesterol and lipid metabolism [72,74]. In total, these data strongly indicate that microRNAs play a central role in sculpting the circadian gene expression profile and, in turn, regulate associated physiological and behavioral processes.

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