A blueprint for a synthetic genetic feedback optimizer

György, András; Menezes, Amor A.; Arcak, Murat

doi:10.1038/s41467-023-37903-0

Cited by 4 publications

(4 citation statements)

References 94 publications

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“…As transcriptional circuits designed by current algorithms like Cello [5] are over‐complicated for simple gates (e.g., AND gate), next‐generation platforms integrating multi‐level regulation to design genetically compact, less burdensome circuits should be developed. After successful deployment in novel host contexts, the universal circuits could be diagnosed by RNA sequencing [25] and optimized with active learning methods [26] and feedback optimizers [27].…”

Section: Figurementioning

confidence: 99%

Toward predictable universal genetic circuit design

Gao,

Wang

2024

Quant. Biol.

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Section: Figurementioning

confidence: 99%

Toward predictable universal genetic circuit design

Gao,

Wang

2024

Quant. Biol.

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“…5−7 We refer to such inherent network architecture of biomolecules at thermodynamic equilibrium as the blueprint of a genetic response. 8,9 Combinatorial control is the hallmark of cellular signaling and gene regulation. 10 In many instances, cellular signaling and transcriptional regulation involve switch-like molecular responses to the presence of signaling molecules.…”

Section: ■ Introductionmentioning

confidence: 99%

“…A frequently used conceptual and quantitative model to explore gene expression is that TFs combinatorially recruit or replace RNA polymerase (RNAP) that binds to the promoter by direct physical interactions. TFs and other biomolecules bind with DNA and often form a complex programmable assembly, which is critical in converting the TF inputs into a switching-like transcriptional output. , Exploring such inherent networks is crucial since they act as information processing units at the cellular level. − We refer to such inherent network architecture of biomolecules at thermodynamic equilibrium as the blueprint of a genetic response. , …”

Section: Introductionmentioning

confidence: 99%

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The Blueprint of Logical Decisions in a NF-κB Signaling System

Gautam,

Sinha

2024

ACS Omega

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Nearly identical cells can exhibit substantially different responses to the same stimulus that causes phenotype diversity. Such interplay between phenotype diversity and the architecture of regulatory circuits is crucial since it determines the state of a biological cell. Here, we theoretically analyze how the circuit blueprints of NF-κB in cellular environments are formed and their role in determining the cells’ metabolic state. The NF-κB is a collective name for a developmental conserved family of five different transcription factors that can form homodimers or heterodimers and often promote DNA looping to reprogram the inflammatory gene response. The NF-κB controls many biological functions, including cellular differentiation, proliferation, migration, and survival. Our model shows that nuclear localization of NF-κB differentially promotes logic operations such as AND, NAND, NOR, and OR in its regulatory network. Through the quantitative thermodynamic model of transcriptional regulation and systematic variation of promoter–enhancer interaction modes, we can account for the origin of various logic gates as formed in the NF-κB system. We further show that the interconversion or switching of logic gates yielded under systematic variations of the stimuli activity and DNA looping parameters. Such computation occurs in regulatory and signaling pathways in individual cells at a molecular scale, which one can exploit to design a biomolecular computer.

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Competition and evolutionary selection among core regulatory motifs in gene expression control

Gyorgy

2023

Nat Commun

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Gene products that are beneficial in one environment may become burdensome in another, prompting the emergence of diverse regulatory schemes that carry their own bioenergetic cost. By ensuring that regulators are only expressed when needed, we demonstrate that autoregulation generally offers an advantage in an environment combining mutation and time-varying selection. Whether positive or negative feedback emerges as dominant depends primarily on the demand for the target gene product, typically to ensure that the detrimental impact of inevitable mutations is minimized. While self-repression of the regulator curbs the spread of these loss-of-function mutations, self-activation instead facilitates their propagation. By analyzing the transcription network of multiple model organisms, we reveal that reduced bioenergetic cost may contribute to the preferential selection of autoregulation among transcription factors. Our results not only uncover how seemingly equivalent regulatory motifs have fundamentally different impact on population structure, growth dynamics, and evolutionary outcomes, but they can also be leveraged to promote the design of evolutionarily robust synthetic gene circuits.

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A blueprint for a synthetic genetic feedback optimizer

Cited by 4 publications

References 94 publications

Toward predictable universal genetic circuit design

Toward predictable universal genetic circuit design

The Blueprint of Logical Decisions in a NF-κB Signaling System

Competition and evolutionary selection among core regulatory motifs in gene expression control

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