MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale

• Published in: eLife Vol. 3; p. e02510
• Main Authors: Du, Ngoc-Hien, Arpat, Alaaddin Bulak, De Matos, Mara, Gatfield, David
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.05.2014; eLife Sciences Publications, Ltd
• Subjects: 3' Untranslated Regions - genetics; Animals; Biological Clocks - genetics; Biomarkers - metabolism; Biosynthesis; Cells, Cultured; circadian clock; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; DEAD-box RNA Helicases - metabolism; Dicer knockout; Gene expression; Gene Expression Regulation; Gene regulation; Genes and Chromosomes; Genes, Reporter; Genome; Genomics; Genomics and Evolutionary Biology; Hepatocytes - metabolism; Hypotheses; Liver; Liver - metabolism; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Models, Biological; Ontology; Oscillations; Period Circadian Proteins - metabolism; Post-transcription; Proteins; Reproducibility of Results; Ribonuclease III - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sequence Analysis, RNA; Transcription factors; Transcription, Genetic; Transcriptome - genetics; miRNA; liver; Dicer knockout; circadian clocks
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.02510

A considerable proportion of mammalian gene expression undergoes circadian oscillations. Post-transcriptional mechanisms likely make important contributions to mRNA abundance rhythms. We have investigated how microRNAs (miRNAs) contribute to core clock and clock-controlled gene expression using mice in which miRNA biogenesis can be inactivated in the liver. While the hepatic core clock was surprisingly resilient to miRNA loss, whole transcriptome sequencing uncovered widespread effects on clock output gene expression. Cyclic transcription paired with miRNA-mediated regulation was thus identified as a frequent 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 few mRNA rhythms were actually generated by miRNAs. Overall, our study suggests that miRNAs function to adapt clock-driven gene expression to tissue-specific requirements. Finally, we pinpoint several miRNAs predicted to act as modulators of rhythmic transcripts, and identify rhythmic pathways particularly prone to miRNA regulation. The rising and setting of the sun have long driven the schedules of humans and other mammals. This 24-hr cycle influences many behavioural and physiological changes, including alertness, body temperature, and sleep. A region in the brain acts as a master clock that regulates these daily cycles, which are called circadian rhythms. Signals from the brain's master clock turn on and off ‘core clock genes’ in cells, which trigger cycles that cause some proteins to be produced in a circadian rhythm. The rhythm is specialized to a particular tissue or organ, and may help them to carry out their designated daily tasks. However, circadian rhythms might also be produced in other ways that do not involve these genes. Messenger RNA (mRNA) molecules have a central role in the production of proteins, and in the mouse liver, up to 15% of mRNA molecules are produced in circadian cycles. The liver performs essential tasks that control metabolism–including that of carbohydrates, fats, and cholesterol. Precisely timing when certain mRNAs and proteins reach peaks and troughs in their activities to coincide with mealtimes is important for nutrients to be properly processed. Other RNA molecules called microRNAs influence how mRNA molecules are translated into proteins. Now Du, Arpat et al. have looked at the influence of microRNAs on circadian rhythms in the mouse liver in greater detail. These experiments, which involved ‘knocking out’ a gene that is essential for the production of microRNAs, show that rather than setting the mRNA rhythms, the microRNAs appear to adjust them to meet the specific needs of the liver. Targeting specific microRNA molecules may reveal new strategies to tweak these rhythms, which could help to improve conditions when metabolic functions go wrong.