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dc.contributor.author
Folcher, Marc
dc.contributor.author
Xie, Mingqi
dc.contributor.author
Spinnler, Andrea
dc.contributor.author
Fussenegger, Martin
dc.date.accessioned
2019-04-02T15:56:53Z
dc.date.available
2017-06-10T20:05:30Z
dc.date.available
2019-04-02T15:56:53Z
dc.date.issued
2013-07
dc.identifier.other
10.1093/nar/gkt405
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/70486
dc.identifier.doi
10.3929/ethz-b-000070486
dc.description.abstract
Synthetic biology has significantly advanced the design of synthetic control devices, gene circuits and networks that can reprogram mammalian cells in a trigger-inducible manner. Prokaryotic helix-turn-helix motifs have become the standard resource to design synthetic mammalian transcription factors that tune chimeric promoters in a small molecule-responsive manner. We have identified a family of Actinomycetes transcriptional repressor proteins showing a tandem TetR-family signature and have used a synthetic biology-inspired approach to reveal the potential control dynamics of these bi-partite regulators. Daisy-chain assembly of well-characterized prokaryotic repressor proteins such as TetR, ScbR, TtgR or VanR and fusion to either the Herpes simplex transactivation domain VP16 or the Krueppel-associated box domain (KRAB) of the human kox-1 gene resulted in synthetic bi- and even tri-partite mammalian transcription factors that could reversibly program their individual chimeric or hybrid promoters for trigger-adjustable transgene expression using tetracycline (TET), γ-butyrolactones, phloretin and vanillic acid. Detailed characterization of the bi-partite ScbR-TetR-VP16 (ST-TA) transcription factor revealed independent control of TET- and γ-butyrolactone-responsive promoters at high and double-pole double-throw (DPDT) relay switch qualities at low intracellular concentrations. Similar to electromagnetically operated mechanical DPDT relay switches that control two electric circuits by a fully isolated low-power signal, TET programs ST-TA to progressively switch from TetR-specific promoter-driven expression of transgene one to ScbR-specific promoter-driven transcription of transgene two while ST-TA flips back to exclusive transgene 1 expression in the absence of the trigger antibiotic. We suggest that natural repressors and activators with tandem TetR-family signatures may also provide independent as well as DPDT-mediated control of two sets of transgenes in bacteria, and that their synthetic transcription-factor analogs may enable the design of compact therapeutic gene circuits for gene and cell-based therapies.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Oxford University Press
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/3.0/
dc.title
Synthetic mammalian trigger-controlled bipartite transcription factors
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 3.0 Unported
dc.date.published
2013-05-17
ethz.journal.title
Nucleic acids research
ethz.journal.volume
41
en_US
ethz.journal.issue
13
en_US
ethz.pages.start
e134
en_US
ethz.size
17 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.nebis
000038633
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.::03694 - Fussenegger, Martin / Fussenegger, Martin
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.::03694 - Fussenegger, Martin / Fussenegger, Martin
ethz.date.deposited
2017-06-10T20:07:49Z
ethz.source
ECIT
ethz.identifier.importid
imp593650e1bd04c42462
ethz.ecitpid
pub:111631
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-18T13:45:28Z
ethz.rosetta.lastUpdated
2019-04-02T15:57:19Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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