A bistable genetic switch based on designable DNA-binding domains

Tina Lebar, Urban Bezeljak, Anja Golob, Miha Jerala, Lucija Kadunc, Boštjan Pirš, Martin Stražar, Dušan Vučko, Uroš Zupančič, Mojca Benčina, Vida Forstnerič, Rok Gaber, Jan Lonzarić, Andreja Majerle, Alja Oblak, Anže Smole and Roman Jerala ()
Additional contact information
Tina Lebar: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Urban Bezeljak: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Anja Golob: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Miha Jerala: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Lucija Kadunc: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Boštjan Pirš: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Martin Stražar: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Dušan Vučko: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Uroš Zupančič: Slovenian iGEM Team 2012, National Institute of Chemistry and University of Ljubljana
Mojca Benčina: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Vida Forstnerič: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Rok Gaber: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Jan Lonzarić: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Andreja Majerle: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Alja Oblak: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Anže Smole: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia
Roman Jerala: National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Bistable switches are fundamental regulatory elements of complex systems, ranging from electronics to living cells. Designed genetic toggle switches have been constructed from pairs of natural transcriptional repressors wired to inhibit one another. The complexity of the engineered regulatory circuits can be increased using orthogonal transcriptional regulators based on designed DNA-binding domains. However, a mutual repressor-based toggle switch comprising DNA-binding domains of transcription-activator-like effectors (TALEs) did not support bistability in mammalian cells. Here, the challenge of engineering a bistable switch based on monomeric DNA-binding domains is solved via the introduction of a positive feedback loop composed of activators based on the same TALE domains as their opposing repressors and competition for the same DNA operator site. This design introduces nonlinearity and results in epigenetic bistability. This principle could be used to employ other monomeric DNA-binding domains such as CRISPR for applications ranging from reprogramming cells to building digital biological memory.

Date: 2014
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DOI: 10.1038/ncomms6007

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