A Period1 inducer specifically advances circadian clock in mice
- Yoshifumi Takahata
- Yuki Kasashima
- Takuya Yoshioka
- Shusei Yashiki
- Justina Kulikauskaite
- Tomoaki Matsuura
- Yuki Ohba
- Hideaki Hasegawa
- Naoki Yuri
- Nagisa Iwai
- Nanako Otsu
- Mikiya Kitakata
- Yuta Kitaguchi
- Haruki Furune
- Chihiro Omori
- Mutsumi Mukai
- Yuki Komamura-Kohno
- Yi-Ying Huang
- Matsumi Hirose
- Nobuya Koike
- Yoichi Yamada
- Kazuo Nakazawa
- Kumiko Ui-Tei
- Yoshiyuki Sakaki
- Rika Numano
- Koichiro Uriu
- Hajime Tei
2026-01-23
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.