A Period1 inducer specifically advances circadian clock in mice

• 成果类型: Article
• 署名作者: Takahata, Yoshifumi; Kasashima, Yuki; Yoshioka, Takuya; Yashiki, Shusei; Kulikauskaite, Justina; Matsuura, Tomoaki; Ohba, Yuki; Hasegawa, Hideaki; Yuri, Naoki; Iwai, Nagisa; Otsu, Nanako; Kitakata, Mikiya; Kitaguchi, Yuta; Furune, Haruki; Omori, Chihiro; Mukai, Mutsumi; Komamura-Kohno, Yuki; Huang, Yi-Ying; Hirose, Matsumi; Koike, Nobuya; Yamada, Yoichi; Nakazawa, Kazuo; Ui-Tei, Kumiko; Sakaki, Yoshiyuki; Numano, Rika; Uriu, Koichiro; Tei, Hajime
• 署名单位: University of Osaka; University of Osaka; Kanazawa University; Kanazawa University; Mitsubishi International Corporation (MIC); Mitsubishi Kagaku Institute of Life Sciences (MITILS); Kyoto Prefectural University of Medicine; Toyohashi University of Technology; University of Tokyo; Institute of Science Tokyo; University of Tokyo; Toyohashi University of Technology; Institute of Science Tokyo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2509943123
• 发表日期: 2026-01-27
• 页码: e2509943123
• 关键词: mammalian circadian rhythms; clock gene; Period1 inducer; INDUCED PHASE-SHIFTS; transcriptional architecture; suprachiasmatic nucleus; gene-expression; light; MPER1; identification; REENTRAINMENT; cryptochrome; rhythms

摘要

West-to-east transmeridian flights are more disruptive than east-to-west ones due to challenges in advancing the human circadian clock. Transient mammalian Period1 (Per1) induction was predicted to predominantly advance the clock phase in our previous work. Here, we unravel a specific Per1 inducer, Mic-628, enabling abrupt phase advance in mouse behavioral rhythms, regardless of the timing of oral administration. Mic-628-treated mice re-entrain to phase-advanced light-dark cycles significantly faster. The direct interaction between Mic-628 and CRYPTOCHROME1 (CRY1) does not simply inhibit CRY1 repressor activity. Instead, the interaction facilitates the CLOCK-BMAL1 assembly, ensuring highly specific induction via a tandem E-box motif upstream of the Per1 promoter. Importantly, Mic-628-driven Per1 induction is repressed by PER1 itself. Mathematical modeling indicates that both the CRY1-and PER1-mediated transcriptional regulation fix the phase of Per1 induction irrespective of intake time, thereby predominantly advancing the clock phase. These findings underscore the potential of selective Per expression as a therapeutic approach for human circadian rhythm disorders.