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The Effect of Compositional Context on Synthetic Gene Networks

Yeung, Enoch and Dy, Aaron J. and Martin, Kyle B. and Ng, Andrew H. and Del Vecchio, Domitilla and Beck, James L. and Collins, James J. and Murray, Richard M. (2016) The Effect of Compositional Context on Synthetic Gene Networks. . (Submitted) https://resolver.caltech.edu/CaltechAUTHORS:20170313-102144883

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Abstract

It is well known that synthetic gene expression is highly sensitive to how 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 compositional context, or spatial arrangement, 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 significantly alters transcription levels in synthetic gene networks. We demonstrate that key characteristics of gene induction, such as ultra-sensitivity and dynamic range, strongly depend on compositional context. We postulate that supercoiling can be used to explain this interference and validate this hypothesis through modeling and a series of in vitro supercoiling relaxation experiments. This compositional interference enables a novel form of feedback in synthetic gene networks. We illustrate the use of this feedback by redesigning the toggle switch to incorporate compositional context. We show the context-optimized toggle switch has improved threshold detection and memory properties.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/083329DOIDiscussion Paper
ORCID:
AuthorORCID
Yeung, Enoch0000-0001-7630-7429
Dy, Aaron J.0000-0003-0535-517X
Del Vecchio, Domitilla0000-0001-6472-8576
Murray, Richard M.0000-0002-5785-7481
Additional Information:The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license. This article is a preprint and has not been peer-reviewed. November 30, 2016. We thank Ophelia Venturelli for her invaluable inspiration and guidance in this project, Victoria Hsiao, Jin Park, Anu-Thubagere, Adam Rosenthal for great advice on imaging, David Younger, Ania Baetica, Vincent Noireaux, Clarmyra Hayes, and Zachary Z. Sun for guidance and assistance with TX-TL experiments, and Lea Goentoro, Johann Paulsson, Long Cai, Jennifer Brophy, John Doyle, Eric Klavins, and Julius Lucks for insightful conversations. This work was supported in part by a Charles Lee Powell Foundation Fellowship, a Kanel Foundation Fellowship, a National Science Foundation Graduate Fellowship, National Defense Science and Engineering Graduate Fellowship, Air Force Office of Scientific Research Grant (AFOSR) FA9550-14-1-0060, Defense Threat Reduction Agency Grant HDTRA1-14-1-0006, and Defense Advanced Research Projects Agency Grant HR0011-12-C-0065. The authors have declared that no conflicts of interest exist.
Funders:
Funding AgencyGrant Number
Charles Lee Powell FoundationUNSPECIFIED
John and Ursula Kanel Charitable FoundationUNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Air Force Office of Scientific Research (AFOSR)FA9550-14-1-0060
Defense Threat Reduction AgencyHDTRA1-14-1-0006
Defense Advanced Research Projects Agency (DARPA)HR0011-12-C-0065
Record Number:CaltechAUTHORS:20170313-102144883
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170313-102144883
Official Citation: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
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75057
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:13 Mar 2017 20:48
Last Modified:11 Nov 2020 22:28

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