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

Russell M. Gordley, Reid E. Williams, Caleb J. Bashor, Jared E. Toettcher, Shude Yan, Wendell A. Lim

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13528-13533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number47
DOIs
StatePublished - Nov 22 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Dynamical control
  • Phosphorylation
  • Synthetic biology

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