MicroRNA-mediated regulation in the mammalian circadian rhythm

Mammalian circadian rhythms have been extensively studied for many years and many computational models have been presented. Most of the circadian rhythms are based on interlocked positive and negative feedback loops involving coding regions of some ‘clock’ genes. Recent works have implicated that microRNAs (miRNAs) may play crucial roles in modulating the circadian clock. Here we develop a computational model involving four genes, Per, Cry, Bmal1, and Clock, and two miRNAs, miRNA-219 and miRNA-132, to show their post-transcriptional roles in the modulation of the circadian rhythm. The model is based on experimental observations, by which the miRNAs are incorporated into a classic model including only coding genes. In agreement with experimental observations, the model predicts that miRNA-mediated regulation plays critical roles in modulating the circadian clock. In addition, parameter sensitivity analysis indicates that the period of circadian rhythm with miRNA-mediated regulation is more insensitive to perturbations, showing that the miRNA-mediated regulation can enhance the robustness of the circadian rhythms. This study may help us understand the microRNA-mediated regulation in the mammalian circadian rhythm more clearly.

► We present a model for the circadian rhythm involving miRNA-219 and miRNA-132.
► In a certain range of parameter values, the model produces sustained oscillations.
► The model indicates that miRNA-219 expression fine-tunes the length of the circadian period.
► The model also shows miRNA-132 attenuates the entraining effect of light.
► The miRNA-mediated regulation can enhance the robustness of the circadian rhythm.