Post-transcriptional modulators and mediators of the circadian clock

The endogenous circadian timekeeping system drives ~24-h rhythms in gene expression and rhythmically coordinates the physiology, metabolism and behavior in a wide range of organisms. Regulation at various levels is important for the accurate functioning of this circadian timing system. The core circadian oscillator consists of an interlocked transcriptional-translational negative feedback loop (TTFL) that imposes a substantial delay between the accumulation of clock gene mRNA and its protein to generate 24-h oscillations. This TTFL mediated daily oscillation of clock proteins is further fine-tuned by post-translational modifications that regulate the clock protein stability, interaction with other proteins and subcellular localization. Emerging evidence from various studies indicates that besides TTFL and post-translational modifications, post-transcriptional regulation plays a key role in shaping the rhythmicity of mRNAs and to delay the accumulation of clock proteins in relation to their mRNAs. In this review, we summarize the current knowledge on the importance of post-transcriptional regulatory mechanisms such as splicing, polyadenylation, the role of RNA-binding proteins, RNA methylation and microRNAs in the context of shaping the circadian rhythmicity in Drosophila and mammals. In particular, we discuss microRNAs, an important player in post-transcriptional regulation of core-clock machinery, circadian neural circuit, clock input, and output pathways. Furthermore, we provide an overview of the microRNAs that exhibit diurnal rhythm in expression and their role in mediating rhythmic physiological processes.