MicroRNAs Shape Circadian Hepatic Gene Expression on a Transcriptome-Wide Scale

Introduction: A considerable proportion of mammalian gene expression undergoes circadian oscillations. Post-transcriptional mechanisms likely make important contributions to mRNA abundance rhythms. Aim: We have investigated how microRNAs contribute to core clock and clock-controlled gene expression using mice in which microRNA biogenesis can be inactivated in the liver. Results: While the hepatic core clock was surprisingly resilient to microRNA loss, whole transcriptome sequencing uncovered widespread effects on clock ouput gene expression. Cyclic transcription paired with microRNA-mediated regulation was thus identified as a widespread phenomenon that affected up to 30% of the rhythmic transcriptome and served to post-transcriptionally adjust the phases and amplitudes of rhythmic mRNA accumulation. However, only a few mRNA rhythms were actually generated by microRNAs. Finally, we pinpoint several microRNAs predicted to act as modulators of rhythmic transcripts, and identify rhythmic pathways particularly prone to microRNA regulation. Conclusion: Our study provides a comprehensive analysis of miRNA activity in shaping hepatic circadian gene expression and can serve as a valuable resource for further investigations into the regulatory roles that miRNAs play in liver gene expression and physiology. Overall design: RNA-Seq of rRNA-depleted total RNAs from two independent full time series around-the-clock of Dicer knockout and control mouse livers

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Du NH, Arpat AB, De Matos M, Gatfield D