Model-guided design of single-cargo, dual-attractor gene circuits
- 1Massachusetts Institute of Technology
Abstract
Dual-attractor gene networks program distinct states, guiding native cellular decision-making processes such as differentiation. Synthetic dual-attractor circuits (DACs) emulate native gene networks, directing cells to two different states starting from a single, genetically uniform population. However, existing DAC designs for mammalian cells often require multiple genetic cargoes, limiting their application to control cell fate in therapeutically relevant contexts. Here, we leverage model-guided tuning of compact biochemical and biophysical layers of regulation to program two cellular states using a single-cargo DAC. Through activator selection and layering microRNA-mediated mutual repression, we identify and resolve an imbalance between modules that biases states, allowing us to achieve balanced adoption of both states without relying on copy-number variation. Consolidating this optimized DAC into a single cargo, we use gene syntax to minimize bias, generating two balanced states from a single cargo of less than 11 kilobases. Overall, this work establishes design rules for combined biochemical and biophysical tuning of DACs to generate balanced cell states from a single-cargo design, paving the way for programming divergent cell-state trajectories and dual-fate systems.
Related
- A single attractor governs the population dynamics of marine fishes worldwide
- Beyond the attractor: closed-loop stimulation design for learning multistable neural dynamics
- A split attractor design for rapidly writing a navigational goal
- Design Tradeoffs in High Resolution, Large Field-of-View 3D All-Optical Control of Neural Circuits
- Biomechanics-guided computational design of virtual terrestrial vertebrate morphogenesis
BibTeX
@misc{peterman2026modelguided,
title = {{Model-guided design of single-cargo, dual-attractor gene circuits}},
author = {E. L. Peterman and N. Nolan and P. M. Naydenkov and D. R. Godavarti and D. Del Vecchio and K. E. Galloway},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760260},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760260v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Model-guided design of single-cargo, dual-attractor gene circuits
AU - E. L. Peterman
AU - N. Nolan
AU - P. M. Naydenkov
AU - D. R. Godavarti
AU - D. Del Vecchio
AU - K. E. Galloway
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760260
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760260v1
AB - Dual-attractor gene networks program distinct states, guiding native cellular decision-making processes such as differentiation. Synthetic dual-attractor circuits (DACs) emulate native gene networks, directing cells to two different states starting from a single, genetically uniform population. However, existing DAC designs for mammalian cells often require multiple genetic cargoes, limiting their application to control cell fate in therapeutically relevant contexts. Here, we leverage model-guided tuning of compact biochemical and biophysical layers of regulation to program two cellular states using a single-cargo DAC. Through activator selection and layering microRNA-mediated mutual repression, we identify and resolve an imbalance between modules that biases states, allowing us to achieve balanced adoption of both states without relying on copy-number variation. Consolidating this optimized DAC into a single cargo, we use gene syntax to minimize bias, generating two balanced states from a single cargo of less than 11 kilobases. Overall, this work establishes design rules for combined biochemical and biophysical tuning of DACs to generate balanced cell states from a single-cargo design, paving the way for programming divergent cell-state trajectories and dual-fate systems.
ER -