Post-transcriptional modulators and mediators of the circadian clock

Abstract

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.

Keywords: Circadian; input; mRNA; microRNA; output; post-transcriptional.

Figure 1. microRNA mediated regulation of circadian rhythm in Drosophila

Circadian timing system is depicted with three primary components such as input pathways, the central oscillator and the output pathways. Environmental cues such as light and temperature entrain the central oscillator. Central oscillator shown in the schematic cross section of the fly brain comprises of ~150 clock neurons and it consists of large ventrolateral neurons (l-LNvs, yellow), Small ventrolateral neurons (s-LNvs, blue), lateral posterior neuron (LPN- green), dorsolateral neurons (LNds, red), and dorsal neurons (DN1- orange, DN2-blue open circle, DN3-black). The endogenous rhythmicity of the central oscillator is driven by interlocked primary and secondary transcriptional-translational feedback loop. The primary feedback loop consists of positive limb component CLK/CYC and a negative limb PER/TIM. VRI and PDP1 in the secondary feedback loop respectively inhibits and activates the transcription of Clk. In addition, the transcription repressor CWO inhibits the transcription of per and tim by competing with CLK-CYC for the E-box binding. Several microRNAs regulate the core clock components, clock neuron excitability, input and output pathways of Drosophila circadian timing system. Blunt end lines denote inhibitory effects. Solid and dashed lines denote known and putative pathways respectively.

Figure 2. microRNA mediated regulation of circadian rhythm in mammals

In mammals, light input is conveyed to the central oscillator suprachiasmatic nucleus (SCN). SCN is located at the base of the hypothalamus as shown in the schematic cross section of the adult mammalian brain. Primary and secondary feedback loops operating in the SCN neurons generates ~24 hour rhythmicity in behaviour and physiological outputs in the peripheral tissues. The primary TTFL consists of the negative arm PER/CRY and a positive arm CLOCK/BMAL1. The secondary feedback loop components REV-ERB and ROR repress and activate the Bmal1 transcription respectively. Furthermore Differentiated embryo chondrocyte (Dec) transcription factor interacts with Bmal1 and inhibits CLOCK/BMAL1 induced transcription. Various microRNAs regulate the core clock components, clock neuron morphology, input and output pathways of mammalian clock system. Blunt end lines denote inhibitory effects. Solid and dashed lines denote known and putative pathways respectively.