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dc.contributor.author
Lillacci, Gabriele
dc.contributor.author
Benenson, Yaakov
dc.contributor.author
Khammash, Mustafa Hani
dc.date.accessioned
2019-03-27T15:56:52Z
dc.date.available
2018-11-09T05:53:33Z
dc.date.available
2018-11-23T17:31:33Z
dc.date.available
2019-03-27T15:56:52Z
dc.date.issued
2018-10-12
dc.identifier.issn
1362-4962
dc.identifier.issn
0301-5610
dc.identifier.other
10.1093/nar/gky795
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/302483
dc.identifier.doi
10.3929/ethz-b-000302483
dc.description.abstract
Tunable induction of gene expression is an essential tool in biology and biotechnology. In spite of that, current induction systems often exhibit unpredictable behavior and performance shortcomings, including high sensitivity to transactivator dosage and plasmid take-up variation, and excessive consumption of cellular resources. To mitigate these limitations, we introduce here a novel family of gene expression control systems of varying complexity with significantly enhanced performance. These include: (i) an incoherent feedforward circuit that exhibits output tunability and robustness to plasmid take-up variation; (ii) a negative feedback circuit that reduces burden and provides robustness to transactivator dosage variability; and (iii) a new hybrid circuit integrating negative feedback and incoherent feedforward that combines the benefits of both. As with endogenous circuits, the complexity of our genetic controllers is not gratuitous, but is the necessary outcome of more stringent performance requirements. We demonstrate the benefits of these controllers in two applications. In a culture of CHO cells for protein manufacturing, the circuits result in up to a 2.6-fold yield improvement over a standard system. In human-induced pluripotent stem cells they enable precisely regulated expression of an otherwise poorly tolerated gene of interest, resulting in a significant increase in the viability of the transfected cells.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Oxford University Press (OUP)
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
dc.title
Synthetic control systems for high performance gene expression in mammalian cells
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 4.0 International
dc.date.published
2018-09-07
ethz.journal.title
Nucleic Acids Research
ethz.journal.volume
46
en_US
ethz.journal.issue
18
en_US
ethz.journal.abbreviated
Nucleic Acids Res.
ethz.pages.start
9855
en_US
ethz.pages.end
9863
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Quantitative in vivo characterization of RNA interference using Synthetic and Systems Biology
en_US
ethz.grant
Theory and Design tools for bio-molecular control systems
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Oxford
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03921 - Khammash, Mustafa / Khammash, Mustafa
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03860 - Benenson, Yaakov / Benenson, Yaakov
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03860 - Benenson, Yaakov / Benenson, Yaakov
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03921 - Khammash, Mustafa / Khammash, Mustafa
ethz.grant.agreementno
149802
ethz.grant.agreementno
743269
ethz.grant.fundername
SNF
ethz.grant.fundername
EC
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.funderDoi
10.13039/501100000780
ethz.grant.program
Projektförderung in Biologie und Medizin (Abteilung III)
ethz.grant.program
H2020
ethz.date.deposited
2018-11-09T05:53:34Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-11-23T17:32:03Z
ethz.rosetta.lastUpdated
2021-02-15T04:08:54Z
ethz.rosetta.versionExported
true
ethz.COinS
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