Cooperative assembly confers regulatory specificity and long-term genetic circuit stability

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dc.citation.firstpage3810en_US
dc.citation.issueNumber18en_US
dc.citation.journalTitleCellen_US
dc.citation.lastpage3.83E+21en_US
dc.citation.volumeNumber186en_US
dc.contributor.authorBragdon, Meghan D. J.en_US
dc.contributor.authorPatel, Nikiten_US
dc.contributor.authorChuang, Jamesen_US
dc.contributor.authorLevien, Ethanen_US
dc.contributor.authorBashor, Caleb J.en_US
dc.contributor.authorKhalil, Ahmad S.en_US
dc.date.accessioned2024-05-08T18:56:08Zen_US
dc.date.available2024-05-08T18:56:08Zen_US
dc.date.issued2023en_US
dc.description.abstractA ubiquitous feature of eukaryotic transcriptional regulation is cooperative self-assembly between transcription factors (TFs) and DNA cis-regulatory motifs. It is thought that this strategy enables specific regulatory connections to be formed in gene networks between otherwise weakly interacting, low-specificity molecular components. Here, using synthetic gene circuits constructed in yeast, we find that high regulatory specificity can emerge from cooperative, multivalent interactions among artificial zinc-finger-based TFs. We show that circuits “wired” using the strategy of cooperative TF assembly are effectively insulated from aberrant misregulation of the host cell genome. As we demonstrate in experiments and mathematical models, this mechanism is sufficient to rescue circuit-driven fitness defects, resulting in genetic and functional stability of circuits in long-term continuous culture. Our naturally inspired approach offers a simple, generalizable means for building high-fidelity, evolutionarily robust gene circuits that can be scaled to a wide range of host organisms and applications.en_US
dc.identifier.citationBragdon, M. D. J., Patel, N., Chuang, J., Levien, E., Bashor, C. J., & Khalil, A. S. (2023). Cooperative assembly confers regulatory specificity and long-term genetic circuit stability. Cell, 186(18), 3810-3825.e18. https://doi.org/10.1016/j.cell.2023.07.012en_US
dc.identifier.digital1-s20-S0092867423007456-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.cell.2023.07.012en_US
dc.identifier.urihttps://hdl.handle.net/1911/115641en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleCooperative assembly confers regulatory specificity and long-term genetic circuit stabilityen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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