A <i>Period1</i> inducer specifically advances circadian clock in mice.

Abstract

West-to-east transmeridian flights are more disruptive than east-to-west ones due to challenges in advancing the human circadian clock. Transient mammalian <i>Period1</i> (<i>Per1</i>) induction was predicted to predominantly advance the clock phase in our previous work. Here, we unravel a specific <i>Per1</i> 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 <i>Per1</i> promoter. Importantly, Mic-628-driven <i>Per1</i> induction is repressed by PER1 itself. Mathematical modeling indicates that both the CRY1- and PER1-mediated transcriptional regulation fix the phase of <i>Per1</i> induction irrespective of intake time, thereby predominantly advancing the clock phase. These findings underscore the potential of selective <i>Per</i> expression as a therapeutic approach for human circadian rhythm disorders.