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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13528-13533. Epub 2016 Nov 7.

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

Author information

1
Howard Hughes Medical Institute, San Francisco, CA 94158.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
3
Graduate Group in Biophysics, University of California, San Francisco, CA 94158.
4
Howard Hughes Medical Institute, San Francisco, CA 94158; wendell.lim@ucsf.edu.

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 long-term 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 dual-timescale 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.

KEYWORDS:

dynamical control; phosphorylation; synthetic biology

PMID:
27821768
PMCID:
PMC5127309
DOI:
10.1073/pnas.1610973113
[Indexed for MEDLINE]
Free PMC Article

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