Reconstitution of circadian clock in synthetic cells reveals principles of timekeeping

Alexander Zhan Tu Li, Andy LiWang and Anand Bala Subramaniam ()
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Alexander Zhan Tu Li: University of California
Andy LiWang: University of California
Anand Bala Subramaniam: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The cyanobacterial circadian clock maintains remarkable precision and synchrony, even in cells with femtoliter volumes. Here, we reconstitute the KaiABC post-translational oscillator (PTO) in giant unilamellar vesicles (GUVs) to investigate underlying mechanisms of this fidelity. We show that our encapsulation methodology replicates native protein variability. With long-term, single-vesicle tracking of circadian rhythms using fluorescent KaiB and confocal microscopy, we find that oscillator fidelity decreases with lower protein levels and smaller vesicle sizes. KaiB membrane association, observed in cyanobacteria, was recapitulated in GUV membranes. A mathematical model incorporating protein stoichiometry limitations suggests that high expression of PTO components and associated regulators (CikA and SasA) buffers stochastic variations in protein levels. Additionally, while the transcription-translation feedback loop contributes minimally to overall fidelity, it is essential for maintaining phase synchrony. These findings demonstrate synthetic cells capable of autonomous circadian rhythms and highlight a generalizable strategy for dissecting emergent biological behavior using minimal systems.

Date: 2025
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DOI: 10.1038/s41467-025-61844-5

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