Engineering dynamical control of cell fate switching using synthetic phospho-regulons

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Abstract

Many cells can sense and respond to time-varying stimuli, selectively triggering changes in cell fate only in response to inputs of a particular duration or frequency. A common motif in dynamically controlled cells is a dual-timescale regulatory network: although longterm fate decisions are ultimately controlled by a slow-timescale switch (e.g., gene expression), input signals are first processed by a fast-timescale signaling layer, which is hypothesized to filter what dynamic information is efficiently relayed downstream. Directly testing the design principles of how dual-timescale circuits control dynamic sensing, however, has been challenging, because most synthetic biology methods have focused solely on rewiring transcriptional circuits, which operate at a single slow timescale. Here, we report the development of a modular approach for flexibly engineering phosphorylation circuits using designed phospho-regulon motifs. By then linking rapid phospho-feedback with slower downstream transcription-based bistable switches, we can construct synthetic dualtimescale circuits in yeast in which the triggering dynamics and the end-state properties of the ON state can be selectively tuned. These phospho-regulon tools thus open up the possibility to engineer cells with customized dynamical control.

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Gordley, R. M., Williams, R. E., Bashor, C. J., Toettcher, J. E., Yan, S., & Lim, W. A. (2016). Engineering dynamical control of cell fate switching using synthetic phospho-regulons. Proceedings of the National Academy of Sciences of the United States of America, 113(47), 13528–13533. https://doi.org/10.1073/pnas.1610973113

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