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

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3810 - 3825.e18

Published: Aug. 1, 2023

A ubiquitous feature of eukaryotic transcriptional regulation is cooperative self-assembly between transcription factors (TFs) and DNA cis-regulatory motifs. It thought that this strategy enables specific regulatory connections to be formed in gene networks otherwise weakly interacting, low-specificity molecular components. Here, using synthetic circuits constructed yeast, we find high specificity can emerge from cooperative, multivalent interactions among artificial zinc-finger-based TFs. We show "wired" the TF assembly are effectively insulated aberrant misregulation host cell genome. As demonstrate experiments mathematical models, mechanism sufficient rescue circuit-driven fitness defects, resulting genetic functional stability long-term continuous culture. Our naturally inspired approach offers a simple, generalizable means for building high-fidelity, evolutionarily robust scaled wide range organisms applications.

Language: Английский

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Gout therapeutics and drug delivery

Journal of Controlled Release, Journal Year: 2023, Volume and Issue: 362, P. 728 - 754

Published: Sept. 21, 2023

Language: Английский

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Synthetic protein circuits for programmable control of mammalian cell death

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2785 - 2800.e16

Published: April 23, 2024

Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific programs in target could similarly remove while appropriately modulating responses. However, actively influence their modes response to natural signals, making it challenging control modes. Here, we introduce naturally inspired "synpoptosis" that proteolytically regulate engineered executioner proteins mammalian death. These direct modes, respond combinations protease inputs, selectively cells. Furthermore, synpoptosis can be transmitted intercellularly, offering a foundation for engineering synthetic killer induce desired without self-destruction. Together, these results lay groundwork programmable

Language: Английский

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Development of compact transcriptional effectors using high-throughput measurements in diverse contexts

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

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Engineering native biological complexity from the inside–out and outside–in

Nature Chemical Engineering, Journal Year: 2024, Volume and Issue: 1(1), P. 2 - 5

Published: Jan. 11, 2024

Language: Английский

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Orthogonal inducible control of Cas13 circuits enables programmable RNA regulation in mammalian cells

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

RNA plays an indispensable role in mammalian cell functions. Cas13, a class of RNA-guided ribonuclease, is flexible tool for modifying and regulating coding non-coding RNAs, with enormous potential creating new However, the lack control over Cas13 activity has limited its engineering capability. Here, we present CRISTAL (Control Inducible SpliT CAs13 Orthologs Exogenous Ligands) platform. powered by collection (10 total) orthogonal split inducible effectors that can be turned ON or OFF via small molecules multiple types, providing precise temporal control. Also, engineer logic circuits respond to endogenous signaling exogenous molecule inputs. Furthermore, orthogonality, low leakiness, high dynamic range our Cas13d Cas13b enable design construction robust incoherent feedforward loop, leading near-perfect tunable adaptation response. Finally, using effectors, achieve simultaneous multiplexed genes vitro mice. Together, represents powerful platform precisely dynamics advance elucidate biology.

Language: Английский

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Contextual computation by competitive protein dimerization networks

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Synthetic Gene Circuits for Regulation of Next‐Generation Cell‐Based Therapeutics

Advanced Science, Journal Year: 2023, Volume and Issue: 11(8)

Published: Dec. 21, 2023

Arming human cells with synthetic gene circuits enables to expand their capacity execute superior sensing and response actions, offering tremendous potential for innovative cellular therapeutics. This can be achieved by assembling components from an ever-expanding molecular toolkit, incorporating switches based on transcriptional, translational, or post-translational control mechanisms. review provides examples the three classes of switches, discusses advantages limitations regulate activity therapeutic in vivo. Genetic designed recognize internal disease-associated signals often encode intricate actuation programs that orchestrate a reduction sensed signal, establishing closed-loop architecture. Conversely, engineered detect external physical cues operate open-loop fashion, switching off upon signal exposure. The integration such into next generation chimeric antigen receptor T-cells is already enabling precise calibration immune responses terms magnitude timing, thereby improving potency safety cells. Furthermore, pre-clinical targeting other chronic diseases are gathering increasing attention, this path forward achieving clinical success. With biology at forefront, therapeutics holds great promise groundbreaking treatments.

Language: Английский

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Advancing cellular immunotherapy with macrophages

Life Sciences, Journal Year: 2023, Volume and Issue: 328, P. 121857 - 121857

Published: June 10, 2023

Language: Английский

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A programmable reaction-diffusion system for spatiotemporal cell signaling circuit design

Cell, Journal Year: 2024, Volume and Issue: 187(2), P. 345 - 359.e16

Published: Jan. 1, 2024

Language: Английский

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