Synthetic multistability in mammalian cells
Open accessPublished version of a preprint
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 would allow engineering of multicellular programs that require interactions among distinct cell types. We created 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 a model-based design, we engineered MultiFate circuits that generate as many as 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 expanded with additional transcription factors. These results provide a foundation for engineering multicellular behaviors in mammalian cells.
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Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · see citing works
Regev, A., Teichmann, S. A., Lander, E. S., Amit, I., Benoist, C., Birney, E., Bodenmiller, B., Campbell, P., Carninci, P., Clatworthy, M., et al. (2017) · eLife · doi:10.7554/elife.27041 · Cited by 2,232 · see citing works
Sharova, L. V., Sharov, A. A., Nedorezov, T., Piao, Y., Shaik, N., & Ko, M. S. H. (2009) · DNA Research · doi:10.1093/dnares/dsn030 · Cited by 591 · see citing works
The evolution of cell types in animals: emerging principles from molecular studies
Arendt, D. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2416 · Cited by 525 · see citing works
A comprehensive single cell transcriptional landscape of human hematopoietic progenitors
Pellin, D., Loperfido, M., Baricordi, C., Wolock, S. L., Montepeloso, A., Weinberg, O. K., Biffi, A., Klein, A. M., & Biasco, L. (2019) · Nature Communications · doi:10.1038/s41467-019-10291-0 · Cited by 360 · see citing works
Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
Kueh, H. Y., Champhekar, A., Nutt, S. L., Elowitz, M. B., & Rothenberg, E. V. (2013) · Science · doi:10.1126/science.1240831 · Cited by 273 · see citing works
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- Authors
- Zhu, R., del Rio-Salgado, J. M., Garcia-Ojalvo, J., & Elowitz, M. B.
- Affiliations
- California Institute of Technology (US)
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
- Corresponding author
- Elowitz, Michael B.
- Venue
- Science
- Published
- 2022-01-21
- Volume
- 375
- Issue
- 6578
- Pages
- eabg9765-eabg9765
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4206552026
- Cited by
- 144
- References
- 6
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 31 · 2023: 26 · 2022: 22 · 2021: 3
- FWCI
- 9.47
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- synthetic gene circuits, multistability, cell fate regulation, zinc finger transcription factor, homodimerization, heterodimerization, state switching, multicellular behavior
- MeSH terms
- Animals, Cell Line, Cricetulus, Genetic Engineering, Models, Theoretical, Transcription Factors, Protein Engineering, Transcriptional Activation, Zinc Fingers, CHO Cells, Gene Regulatory Networks, Protein Multimerization, Protein Stability, Synthetic Biology
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