期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 42, 页码 E8855-E8864出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1706611114
关键词
Per2 gene; circadian; miR-24; microRNA; 3'-UTR regulation
资金
- NIH/National Institute of GeneralMedical Sciences (NIGMS) [R01GM114424]
- Welch Foundation [AU-1731]
- NIH/National Institute on Aging Grants [R01AG045828, R01AG045828-04S1]
- NIH Grant [NS099813]
- NARSAD Young Investigator Grant [21267]
- Sumitomo Foundation Grant for Basic Science Research Projects [150056]
- Tomizawa Jun-ichi & Keiko Fund of Molecular Biology Society of Japan for Young Scientists
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP26293048]
- Uehara Memorial Foundation [JSPS 15H04683, JSPS 16H01880]
- NIH/NINDS [NS051278]
- NIH/NIGMS [R01GM112991, R01GM111387]
- NIH/National Institute of Mental Health (NIMH) Silvio O. Conte Center [P50MH074924]
- NIH/NIMH [U01MH61915]
- Grants-in-Aid for Scientific Research [16H01880] Funding Source: KAKEN
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 freerunning periods (similar to 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, Bmal1mRNA 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.
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