Period2 3′-UTR and microRNA-24 regulate circadian rhythms by repressing PERIOD2 protein accumulation

Seung Hee Yoo, Shihoko Kojima, Kazuhiro Shimomura, Nobuya Koike, Ethan D. Buhr, Tadashi Furukawa, Caroline H. Ko, Gabrielle Gloston, Christopher Ayoub, Kazunari Nohara, Bryan A. Reyes, Yoshiki Tsuchiya, Ook Joon Yoo, Kazuhiro Yagita, Choogon Lee, Zheng Chen, Shin Yamazaki, Carla B. Green, Joseph S. Takahashi

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E8855-E8864
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number42
DOIs
Publication statusPublished - Oct 17 2017

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Keywords

  • 3′-UTR regulation
  • Circadian
  • microRNA
  • miR-24
  • Per2 gene

ASJC Scopus subject areas

  • General

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