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

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.

miRNAs Are Required for Generating a Time Delay Critical for the Circadian Oscillator

“…Since it has been proposed that more than one third of human genes are regulated by miRNAs in diverse aspects of cell physiology [33, 34], and multiple miRNA species have been implicated in the molecular clock and output pathways in several model organisms [35–41], it is highly likely that RNAi regulation plays critical roles in the mammalian clock. In an extensive in vivo study, Cheng et al implicated miR-219 and 132 in the time-keeping mechanism: brain-specific miRNA219 was implicated in period determination, while miRNA132 was implicated in photic entrainment [36].…”

Circadian MicroRNAs in Cardioprotection

“…Rhythmic control of microRNA expression appears to be highly conserved and has significant consequences for circadian timing [70]. As such several rhythmically regulated microRNAs were identified.…”

“…This suggests that light might control these microRNAs. Within humans, it would not be surprising to observe a similar pattern of microRNA expression driven by exogenous time cues [70]. In fact, findings on miR-21 expression indicated regulation by light in mice and humans [19].…”

Adaptation of molecular circadian clockwork to environmental changes: a role for alternative splicing and miRNAs

“…In a very elegant study by the Obrietan laboratory [11,60], miR-132 was shown to mediate entrainment of the circadian clock in mice. In brief, the authors identified two miRNAs that are regulated by the circadian and light-induced transcription factor CREB: miR-132 and miR-219.…”