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Phase Separation to Resolve Growth-Related Circuit Failures

Zhang, R.; Yang, W.; Zhang, R.; Rijal, S.; Youssef, A.; Zheng, W.; Tian, X.

2024-11-03 synthetic biology
10.1101/2024.11.01.621586 bioRxiv
Show abstract

Fluctuations in host cell growth poses a significant challenge to synthetic gene circuits, often disrupting circuit function. Existing solutions typically rely on circuit redesign with alternative topologies or additional control elements, yet a broadly applicable approach remains elusive. Here, we introduce a new strategy based on liquid-liquid phase separation (LLPS) to stabilize circuit performance. By engineering a self-activating circuit with transcription factors (TF) fused to an intrinsically disordered region (IDR), we enable the formation of TF condensates at the promoter region, maintaining local TF concentration despite growth-mediated dilution. This condensate formation preserves bistable memory in the self-activating circuit, demonstrating that phase separation can robustly counteract growth fluctuations, offering a novel design principle for resilient synthetic circuits.

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