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.