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The Effect of Compositional Context on Synthetic Gene Networks

Enoch Yeung, Aaron J. Dy, Kyle B. Martin, Andrew H. Ng, Domitilla Del Vecchio, James L. Beck, James J. Collins, Richard M. Murray
doi: https://doi.org/10.1101/083329
Enoch Yeung
1Control & Dynamical Systems, Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA 91125;
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  • For correspondence: eyeung@caltech.edu
Aaron J. Dy
2Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Kyle B. Martin
3Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
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Andrew H. Ng
4Department of Bioengineering, University of California Berkeley, Berkeley, CA 94709;
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Domitilla Del Vecchio
5Department of Mechanical Engineering, Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139;
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James L. Beck
6Department of Civil and Mechanical Engineering, California Institute of Technology, Pasadena, CA;
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James J. Collins
2Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139;
7Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02115;
8Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02115;
9Broad Institute of MIT and Harvard, Cambridge, MA 02142;
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Richard M. Murray
1Control & Dynamical Systems, Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA 91125;
3Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
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SUMMARY

It is well known that synthetic gene expression is highly sensitive to how comprising genetic elements (promoter structure, spacing regions between promoter and coding sequences, ribosome binding sites, etc.) are spatially configured. An important topic that has received far less attention is how the physical layout of entire genes within a synthetic gene network affects their individual expression levels. In this paper we show, both quantitatively and qualitatively, that compositional context can significantly alter expression levels in synthetic gene networks. We also show that these compositional context effects are pervasive both at the transcriptional and translational level. Further, we demonstrate that key characteristics of gene induction, such as ultra-sensitivity and dynamic range, are heavily dependent on compositional context. We postulate that supercoiling can be used to explain these interference effects and validate this hypothesis through modeling and a series of in vitro supercoiling relaxation experiments. On the whole, these results suggest that compositional context introduces feedback in synthetic gene networks. As an illustrative example, we show that a design strategy incorporating compositional context effects can improve threshold detection and memory properties of the toggle switch.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 30, 2016.
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The Effect of Compositional Context on Synthetic Gene Networks
Enoch Yeung, Aaron J. Dy, Kyle B. Martin, Andrew H. Ng, Domitilla Del Vecchio, James L. Beck, James J. Collins, Richard M. Murray
bioRxiv 083329; doi: https://doi.org/10.1101/083329
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The Effect of Compositional Context on Synthetic Gene Networks
Enoch Yeung, Aaron J. Dy, Kyle B. Martin, Andrew H. Ng, Domitilla Del Vecchio, James L. Beck, James J. Collins, Richard M. Murray
bioRxiv 083329; doi: https://doi.org/10.1101/083329

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