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

Oct 5, 2017Proceedings of the National Academy of Sciences of the United States of America

How Period2 RNA and microRNA-24 control daily body clocks by limiting PERIOD2 protein levels

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Abstract

Mice with modified PER2::LUCIFERASE showed more than threefold stronger bioluminescence rhythms than controls.

Mice exhibited lengthened free-running periods of approximately 24.0 hours.
There were greater phase delays following light pulses in the modified mice.
Enhanced temperature compensation was observed in the modified mice.
miR-24 was found to suppress PER2 protein translation, while reversing this inhibition increased PER2 protein levels.
Rhythmic overexpression of PER2 was associated with increased oscillatory amplitude of both mRNA and protein levels, as well as CRY1 protein oscillation.

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We previously created two PER2::LUCIFERASE (PER2::LUC) circadian reporter knockin mice that differ only in the3'-UTR region:, which retains the endogenous3'-UTR and, where the endogenous3'-UTR was replaced by an SV40 late poly(A) signal. To delineate the in vivo functions of3'-UTR, we analyzed circadian rhythms ofmice. Interestingly,mice displayed more than threefold stronger amplitude in bioluminescence rhythms thanmice, and also exhibited lengthened free-running periods (∼24.0 h), greater phase delays following light pulse, and enhanced temperature compensation relative toAnalysis of the3'-UTR sequence revealed that miR-24, and to a lesser degree miR-30, suppressed PER2 protein translation, and the reversal of this inhibition inaugmented PER2::LUC protein level and oscillatory amplitude. Interestingly,mRNA and protein oscillatory amplitude as well as CRY1 protein oscillation were increased inmice, suggesting rhythmic overexpression of PER2 enhances expression ofand other core clock genes. Together, these studies provide important mechanistic insights into the regulatory roles of3'-UTR, miR-24, and PER2 inexpression and core clock function. Per2Per2::Luc Per2Per2::LucSV Per2Per2Per2::LucSV Per2::LucSV Per2::Luc Per2::Luc Per2Per2::LucSV Bmal1Per2::LucSV Per2Per2Per2

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

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