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Synthetic multistability in mammalian cells

View ORCID ProfileRonghui Zhu, Jesus M. del Rio-Salgado, View ORCID ProfileJordi Garcia-Ojalvo, View ORCID ProfileMichael B. Elowitz
doi: https://doi.org/10.1101/2021.02.10.430659
Ronghui Zhu
1Howard Hughes Medical Institute, Division of Biology and Biological Engineering, Broad Center, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA
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Jesus M. del Rio-Salgado
2School of Engineering and Science, Tecnologico de Monterrey, 2000 Avenida Eduardo Monroy Cárdenas, Toluca de Lerdo, Edo. Mex 50110, Mexico
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Jordi Garcia-Ojalvo
3Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
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Michael B. Elowitz
1Howard Hughes Medical Institute, Division of Biology and Biological Engineering, Broad Center, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA
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  • For correspondence: melowitz@caltech.edu
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Abstract

In multicellular organisms, gene regulatory circuits generate thousands of molecularly distinct, mitotically heritable states, through the property of multistability. Designing synthetic multistable circuits would provide insight into natural cell fate control circuit architectures and allow engineering of multicellular programs that require interactions among cells in distinct states. Here we introduce MultiFate, a naturally-inspired, synthetic circuit that supports long-term, controllable, and expandable multistability in mammalian cells. MultiFate uses engineered zinc finger transcription factors that transcriptionally self-activate as homodimers and mutually inhibit one another through heterodimerization. Using model-based design, we engineered MultiFate circuits that generate up to seven states, each stable for at least 18 days. MultiFate permits controlled state-switching and modulation of state stability through external inputs, and can be easily expanded with additional transcription factors. Together, these results provide a foundation for engineering multicellular behaviors in mammalian cells.

Competing Interest Statement

R.Z. and M.B.E. are inventors on a U.S. provisional patent application related to this work.

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  • https://data.caltech.edu/records/1882

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 11, 2021.
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Synthetic multistability in mammalian cells
Ronghui Zhu, Jesus M. del Rio-Salgado, Jordi Garcia-Ojalvo, Michael B. Elowitz
bioRxiv 2021.02.10.430659; doi: https://doi.org/10.1101/2021.02.10.430659
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Synthetic multistability in mammalian cells
Ronghui Zhu, Jesus M. del Rio-Salgado, Jordi Garcia-Ojalvo, Michael B. Elowitz
bioRxiv 2021.02.10.430659; doi: https://doi.org/10.1101/2021.02.10.430659

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