The emerging field of synthetic biology builds gene circuits for scientific, industrial andtherapeutic needs. Adaptability of synthetic gene circuits across different organisms couldenable a synthetic biology pipeline, where circuits are designed in silico, characterized inmicrobes and reimplemented in mammalian settings for practical usage. However, the processesaffecting gene circuit adaptability have not been systematically investigated. Here weconstruct a mammalian version of a negative feedback-based ‘linearizer’ gene circuit previouslydeveloped in yeast. The first nave mammalian prototype was non-functional, but acomputational model suggested that we could recover function by improving gene expressionand protein localization. After rationally developing and combining new parts as the modelsuggested, we regained function and could tune target gene expression in human cells linearlyand precisely as in yeast. The steps we have taken should be generally relevant fortransferring any gene circuit from yeast into mammalian cells.
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