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Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering.

Original publication

DOI

10.1016/j.celrep.2017.08.044

Type

Journal article

Journal

Cell Rep

Publication Date

12/09/2017

Volume

20

Pages

2639 - 2653

Keywords

CRISPR, GPCR, RTK, chimeric receptors, dCas9-VP64, dCas9-synR, genome engineering, split Cas9, synthetic receptors, transcriptional programs