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Review
. 2022 Dec:78:102823.
doi: 10.1016/j.copbio.2022.102823. Epub 2022 Oct 27.

Small molecule-inducible gene regulatory systems in mammalian cells: progress and design principles

Menna Siddiqui  1 , Cristina Tous  1 , Wilson W Wong  2
Affiliations
Review

Small molecule-inducible gene regulatory systems in mammalian cells: progress and design principles

Menna Siddiqui et al. Curr Opin Biotechnol. 2022 Dec.

Abstract

Small molecule-inducible gene circuits are some of the most important tools in biology because they provide a convenient way to exert precise regulation of biological systems. These systems typically are designed to govern gene activation, repression, or disruption at multiple levels, such as through genome modification, transcription, translation, or post-translational regulation of protein activity. Due to their importance, many new systems have been created in the past few years to address different needs or afford orthogonality. They can be broadly characterized based on the inducer used, the mode of regulation, and the effector protein enabling the regulation. Furthermore, each synthetic circuit has varying performance metrics and design considerations. Here, we provide a concise comparison of recently developed tools and recommend standardized metrics for evaluating their performance and potential as biological interrogators or therapeutics.

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Figures

Figure 1.
Figure 1.
Classification of chemical-inducible gene circuits. Inducible gene circuits can be categorized into a) nuclease-based systems b) transcriptional regulators c) post-transcriptional and translational regulators and d) post-translational regulators discussed throughout the text.
Figure 1.
Figure 1.
Classification of chemical-inducible gene circuits. Inducible gene circuits can be categorized into a) nuclease-based systems b) transcriptional regulators c) post-transcriptional and translational regulators and d) post-translational regulators discussed throughout the text.
Figure 2.
Figure 2.
Metrics to evaluate and optimize within inducible gene circuits. Chemical-inducible systems can be characterized in various ways. a) Fold induction calculates the ratio of an induced output to a negative control. b) Signal-to-noise ratio accounts for overlap between on and off populations. c) Cellular viability can be plotted against concentration of inducer as a measure of toxicity. d) Orthogonality matrices measure cross-talk as each effector should ideally have high activity only with its intended pair.
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      • This work describes an ABA-inducible RNA base editor biosensor platform that can perform RNA editing, degradation, or induced translation. Furthermore, they demonstrate this system in-vivo, expanding the toolbox for studying dynamic RNA regulation.