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    Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.


    Takahito Miyake, Yuichi Inoue, Xinyan Shao, Takehito Seta, Yuto Aoki, Khanh Tien Nguyen Pham, Yuichi Shichino, Junko Sasaki, Takehiko Sasaki, Masahito Ikawa, Yoshiaki Yamaguchi, Hitoshi Okamura, Shintaro Iwasaki, Masao Doi. Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm. Cell reports. 2023 Mar 28;42(3):112157

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    PMID: 36882059

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