Genetically encoded assembly recorder temporally resolves cellular histories in cellulo and in vivo

Yan, Y.; Lu, J.; Li, Z.; Zhao, Z.-H.; Shay, T. F.; Wang, S.; Lei, Y.; Wang, Y.; Chen, W.; Parker, P.; Yang, H.; Qi, A.; Sun, Y.; Bergles, D.; Baker, D.; Lin, D.

doi:10.1101/2025.07.16.664392

bioRxiv · 10.1101/2025.07.16.664392

Genetically encoded assembly recorder temporally resolves cellular histories in cellulo and in vivo

Yan, Y.·Lu, J.·Li, Z.·Zhao, Z.-H.·Shay, T. F.·Wang, S.·Lei, Y.·Wang, Y.·Chen, W.·Parker, P.·Yang, H.·Qi, A.·Sun, Y.·Bergles, D.·Baker, D.·Lin, D.

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Abstract

Mapping cellular activity with high spatiotemporal precision in complex tissues is essential for understanding organ physiology, pathology, and regenerative processes. Here, we introduce Granularly Expanding Memory for Intracellular Narrative Integration (GEMINI), an in cellulo recording platform that leverages a computationally designed protein assembly as an intracellular memory device to record individual cells activity histories. GEMINI grows predictably within live cells with minimal interference to cellular functions, capturing cellular activities as tree-ring-like fluorescent patterns in the expanding scaffolds for imaging-based retrospective readout. Absolute chronological information of activity histories was attainable with hour-level accuracy through the integration of fiducial timestamps. GEMINI effectively resolved differential NF{kappa}B-mediated transcriptional changes, distinguishing fast dynamics of 15 minutes, and providing quantifiable signal amplitudes. In a xenograft model, GEMINI recorded inflammation-induced signaling dynamics across tissue with cellular resolution, revealing spatial heterogeneity linked to vascular density. When expressed in the mouse brain, GEMINI exhibited negligible impact on neuronal survival, with animals maintaining normal motor and cognitive behaviors. In physiological contexts, GEMINI successfully resolved both transcriptional changes and activity patterns of neurons in the brain. Together, GEMINI provides a robust and generalizable means for spatiotemporal mapping of cell dynamics underlying physiological and pathological processes in both culture and intact tissues.

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Yan, Y., Lu, J., Li, Z., Zhao, Z.-H., Shay, T. F., Wang, S., Lei, Y., Wang, Y., Chen, W., Parker, P., Yang, H., Qi, A., Sun, Y., Bergles, D., Baker, D., Lin, D.. 2025-07-18. Genetically encoded assembly recorder temporally resolves cellular histories in cellulo and in vivo. https://doi.org/10.1101/2025.07.16.664392

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