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Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9517-22. Epub 2005 Jun 22.

Hysteresis in a synthetic mammalian gene network.

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  • 1Institute for Chemical and Bio-Engineering, Swiss Federal Institute of Technology, Eidgenössische Technische Hochschule Hoenggerberg, HCI F115, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.


Bistable and hysteretic switches, enabling cells to adopt multiple internal expression states in response to a single external input signal, have a pivotal impact on biological systems, ranging from cell-fate decisions to cell-cycle control. We have designed a synthetic hysteretic mammalian transcription network. A positive feedback loop, consisting of a transgene and transactivator (TA) cotranscribed by TA's cognate promoter, is repressed by constitutive expression of a macrolide-dependent transcriptional silencer, whose activity is modulated by the macrolide antibiotic erythromycin. The antibiotic concentration, at which a quasi-discontinuous switch of transgene expression occurs, depends on the history of the synthetic transcription circuitry. If the network components are imbalanced, a graded rather than a quasi-discontinuous signal integration takes place. These findings are consistent with a mathematical model. Synthetic gene networks, which are able to emulate natural gene expression behavior, may foster progress in future gene therapy and tissue engineering initiatives.

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