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Engineering Cell Sensing and Responses Using a GPCR-Coupled CRISPR-Cas System

P. C. Dave P. Dingal, Nathan H. Kipniss, Louai Labanieh, Yuchen Gao, Lei S. Qi
doi: https://doi.org/10.1101/152496
P. C. Dave P. Dingal
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
2Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
3Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA
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Nathan H. Kipniss
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Louai Labanieh
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Yuchen Gao
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
4Cancer Biology Program, Stanford University, Stanford, CA 94305, USA
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Lei S. Qi
1Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
2Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
3Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: stanley.qi@stanford.edu
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Abstract

G-protein coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes, and detects a wide array of physiological cues in the human body. We describe a new molecular device that couples CRISPR-Cas9 programmed genome regulation to natural and synthetic extracellular signals via GPCRs. The design of our synthetic device, named CRISPR ChaCha, displays superior performance over an architecture proposed by the previously reported Tango system. Using a parsimonious mathematical model and gene-reporter assays, we find that CRISPR ChaCha can recruit and activate multiple Cas9 molecules for each GPCR molecule. We also characterize key molecular features that modulate CRISPR ChaCha performance. We adopt the design to diverse GPCRs that sense synthetic and natural ligands including chemokines, mitogens, and fatty acids, and observe efficient conversion of signals to customizable genetic programs in mammalian cells, including regulation of endogenous genes. The new class of CRISPR-coupled GPCRs provides a robust and efficient platform for engineering cells with novel behaviors in response to the diverse GPCR ligand repertoire.

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Posted June 20, 2017.
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Engineering Cell Sensing and Responses Using a GPCR-Coupled CRISPR-Cas System
P. C. Dave P. Dingal, Nathan H. Kipniss, Louai Labanieh, Yuchen Gao, Lei S. Qi
bioRxiv 152496; doi: https://doi.org/10.1101/152496
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Engineering Cell Sensing and Responses Using a GPCR-Coupled CRISPR-Cas System
P. C. Dave P. Dingal, Nathan H. Kipniss, Louai Labanieh, Yuchen Gao, Lei S. Qi
bioRxiv 152496; doi: https://doi.org/10.1101/152496

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