Engineering cell sensing and responses using a GPCR-coupled CRISPR-Cas system

Nathan H. Kipniss, P. C. Dave P. Dingal, Timothy R. Abbott, Yuchen Gao, Haifeng Wang, Antonia A. Dominguez, Louai Labanieh and Lei S. Qi ()
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Nathan H. Kipniss: Stanford University
P. C. Dave P. Dingal: Stanford University
Timothy R. Abbott: Stanford University
Yuchen Gao: Stanford University
Haifeng Wang: Stanford University
Antonia A. Dominguez: Stanford University
Louai Labanieh: Stanford University
Lei S. Qi: Stanford University

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and detect a wide array of cues in the human body. Here we describe a molecular device that couples CRISPR-dCas9 genome regulation to diverse natural and synthetic extracellular signals via GPCRs. We generate alternative architectures for fusing CRISPR to GPCRs utilizing the previously reported design, Tango, and our design, ChaCha. Mathematical modeling suggests that for the CRISPR ChaCha design, multiple dCas9 molecules can be released across the lifetime of a GPCR. The CRISPR ChaCha is dose-dependent, reversible, and can activate multiple endogenous genes simultaneously in response to extracellular ligands. We adopt the design to diverse GPCRs that sense a broad spectrum of ligands, including synthetic compounds, chemokines, mitogens, fatty acids, and hormones. This toolkit of CRISPR-coupled GPCRs provides a modular platform for rewiring diverse ligand sensing to targeted genome regulation for engineering cellular functions.

Date: 2017
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DOI: 10.1038/s41467-017-02075-1

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