Period2 3'-UTR and microRNA-24 Regulate Circadian Rhythms by Repressing PERIOD2 Protein Accumulation

Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):E8855-E8864. doi: 10.1073/pnas.1706611114. Epub 2017 Oct 2.

Abstract

We previously created two PER2::LUCIFERASE (PER2::LUC) circadian reporter knockin mice that differ only in the Per2 3'-UTR region: Per2::Luc, which retains the endogenous Per2 3'-UTR and Per2::LucSV, where the endogenous Per2 3'-UTR was replaced by an SV40 late poly(A) signal. To delineate the in vivo functions of Per2 3'-UTR, we analyzed circadian rhythms of Per2::LucSV mice. Interestingly, Per2::LucSV mice displayed more than threefold stronger amplitude in bioluminescence rhythms than Per2::Luc mice, and also exhibited lengthened free-running periods (∼24.0 h), greater phase delays following light pulse, and enhanced temperature compensation relative to Per2::Luc Analysis of the Per2 3'-UTR sequence revealed that miR-24, and to a lesser degree miR-30, suppressed PER2 protein translation, and the reversal of this inhibition in Per2::LucSV augmented PER2::LUC protein level and oscillatory amplitude. Interestingly, Bmal1 mRNA and protein oscillatory amplitude as well as CRY1 protein oscillation were increased in Per2::LucSV mice, suggesting rhythmic overexpression of PER2 enhances expression of Per2 and other core clock genes. Together, these studies provide important mechanistic insights into the regulatory roles of Per2 3'-UTR, miR-24, and PER2 in Per2 expression and core clock function.

Keywords: 3′-UTR regulation; Per2 gene; circadian; miR-24; microRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Circadian Clocks / genetics
  • Circadian Rhythm / physiology*
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Luciferases / genetics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Protein Biosynthesis
  • Temperature

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Mirn24 microRNA, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Luciferases