Toward construction of a self-sustained clock-like expression system based on the mammalian circadian clock

Biotechnology and Bioengineering
Dmitri Chilov, Martin Fussenegger

Abstract

Despite recent advances in circadian biology, detailed understanding of how a biological pacemaker system is assembled, maintained, and regulated continues to be a significant challenge. We have assembled and characterized a first-generation, regulatable, self-sustained clock-like expression system based on key components of the mammalian circadian clock. The molecular setup of the clock-like oscillator was reduced to the core set of positive and negative elements common to all known circadian pacemakers. Sophisticated tetracycline-responsive multi-cistronic expression integrated with forefront lentiviral transduction tools enabled autoregulated reporter transgene expression in a human cell line. We characterized transgene expression kinetics of an artificial oscillator and showed that its expression profiles could be modulated by a serum shock and administration of regulating tetracycline antibiotics. Design of a generic mammalian clock-like expression system will offer novel opportunities to study circadian biology and may provide a unique tool for rhythmic expression of desired transgenes fostering advances in biopharmaceutical manufacturing, gene therapy, and tissue engineering.

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Citations

Feb 3, 2009·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·G Russo, M Di Bernardo
Mar 4, 2010·Nucleic Acids Research·Marcel TiggesMartin Fussenegger
Aug 10, 2010·Nucleic Acids Research·David Greber, Martin Fussenegger
Aug 17, 2010·Current Opinion in Biotechnology·Etsuo A SusakiHiroki R Ueda
Sep 19, 2009·Current Opinion in Biotechnology·Marcel Tigges, Martin Fussenegger
Jul 3, 2007·Journal of Biotechnology·David Greber, Martin Fussenegger
Dec 10, 2016·The Journal of Cell Biology·Melina MathurChristina D Smolke
Jan 17, 2009·Nature·Marcel TiggesMartin Fussenegger
Jun 3, 2018·Nature Reviews. Molecular Cell Biology·Mingqi Xie, Martin Fussenegger
Dec 17, 2020·Viruses·Audrey PageFrançois-Loïc Cosset

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