A genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms

Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2020454118. doi: 10.1073/pnas.2020454118.


The regulatory mechanisms of circadian rhythms have been studied primarily at the level of the transcription-translation feedback loops of protein-coding genes. Regulatory modules involving noncoding RNAs are less thoroughly understood. In particular, emerging evidence has revealed the important role of microRNAs (miRNAs) in maintaining the robustness of the circadian system. To identify miRNAs that have the potential to modulate circadian rhythms, we conducted a genome-wide miRNA screen using U2OS luciferase reporter cells. Among 989 miRNAs in the library, 120 changed the period length in a dose-dependent manner. We further validated the circadian regulatory function of an miRNA cluster, miR-183/96/182, both in vitro and in vivo. We found that all three members of this miRNA cluster can modulate circadian rhythms. Particularly, miR-96 directly targeted a core circadian clock gene, PER2. The knockout of the miR-183/96/182 cluster in mice showed tissue-specific effects on circadian parameters and altered circadian rhythms at the behavioral level. This study identified a large number of miRNAs, including the miR-183/96/182 cluster, as circadian modulators. We provide a resource for further understanding the role of miRNAs in the circadian network and highlight the importance of miRNAs as a genome-wide layer of circadian clock regulation.

Keywords: circadian rhythms; genome-wide screen; miR-183/96/182 cluster; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Circadian Rhythm / genetics*
  • Circadian Rhythm / radiation effects
  • Gene Expression Regulation / genetics*
  • Gene Expression Regulation / radiation effects
  • Gene Knock-In Techniques
  • Gene Knockout Techniques
  • Genomics
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Lung / metabolism
  • Lung / radiation effects
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Multigene Family
  • Organ Specificity
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • Retina / metabolism
  • Retina / radiation effects
  • Suprachiasmatic Nucleus / metabolism
  • Suprachiasmatic Nucleus / radiation effects
  • Time Factors


  • MIRN183 microRNA, human
  • MIRN96 microRNA, human
  • MicroRNAs
  • Mirn182 microRNA, human
  • PER2 protein, human
  • Period Circadian Proteins
  • Luciferases