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Complex signal processing in synthetic gene circuits using cooperative regulatory assemblies

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Science  10 May 2019:
Vol. 364, Issue 6440, pp. 593-597
DOI: 10.1126/science.aau8287

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Cooperativity in synthetic gene circuits

Synthetic biologists would like to be able to make gene regulatory circuits that mimic key properties of eukaryotic gene regulation. Taking a cue from multimeric transcription factor complexes, Bashor et al. developed synthetic transcriptional circuits that produce nonlinear behavior from cooperativity (see the Perspective by Ng and El-Samad). Their system uses clamp proteins with multiple protein-interaction domains. Circuit behavior can be tuned by altering the number or affinities of the interactions according to a mathematical model. The authors created synthetic circuits with desired functions common in biology, for example, switch-like behavior or Boolean decision functions.

Science, this issue p. 593; see also p. 531

Abstract

Eukaryotic genes are regulated by multivalent transcription factor complexes. Through cooperative self-assembly, these complexes perform nonlinear regulatory operations involved in cellular decision-making and signal processing. In this study, we apply this design principle to synthetic networks, testing whether engineered cooperative assemblies can program nonlinear gene circuit behavior in yeast. Using a model-guided approach, we show that specifying the strength and number of assembly subunits enables predictive tuning between linear and nonlinear regulatory responses for single- and multi-input circuits. We demonstrate that assemblies can be adjusted to control circuit dynamics. We harness this capability to engineer circuits that perform dynamic filtering, enabling frequency-dependent decoding in cell populations. Programmable cooperative assembly provides a versatile way to tune the nonlinearity of network connections, markedly expanding the engineerable behaviors available to synthetic circuits.

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