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Cooperative assembly confers regulatory specificity and long-term genetic circuit stability.
Bragdon, Meghan D J; Patel, Nikit; Chuang, James; Levien, Ethan; Bashor, Caleb J; Khalil, Ahmad S.
Afiliación
  • Bragdon MDJ; Biological Design Center, Boston University, Boston, MA 02215, USA; Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, Boston, MA 02215, USA.
  • Patel N; Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
  • Chuang J; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Levien E; Department of Mathematics, Dartmouth College, Hanover, NH 03755, USA.
  • Bashor CJ; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Biosciences, Rice University, Houston, TX 77030, USA.
  • Khalil AS; Biological Design Center, Boston University, Boston, MA 02215, USA; Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineer
Cell ; 186(18): 3810-3825.e18, 2023 08 31.
Article en En | MEDLINE | ID: mdl-37552983
A 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Redes Reguladoras de Genes Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Redes Reguladoras de Genes Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos