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Engineering digitizer circuits for chemical and genetic screens in human cells

Nicole M. Wong, Elizabeth Frias, Frederic D. Sigoillot, Justin H. Letendre, Marc Hild () and Wilson W. Wong ()
Additional contact information
Nicole M. Wong: Boston University
Elizabeth Frias: Novartis Institutes for BioMedical Research
Frederic D. Sigoillot: Novartis Institutes for BioMedical Research
Justin H. Letendre: Boston University
Marc Hild: Novartis Institutes for BioMedical Research
Wilson W. Wong: Boston University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Cell-based transcriptional reporters are invaluable in high-throughput compound and CRISPR screens for identifying compounds or genes that can impact a pathway of interest. However, many transcriptional reporters have weak activities and transient responses. This can result in overlooking therapeutic targets and compounds that are difficult to detect, necessitating the resource-consuming process of running multiple screens at various timepoints. Here, we present RADAR, a digitizer circuit for amplifying reporter activity and retaining memory of pathway activation. Reporting on the AP-1 pathway, our circuit identifies compounds with known activity against PKC-related pathways and shows an enhanced dynamic range with improved sensitivity compared to a classical reporter in compound screens. In the first genome-wide pooled CRISPR screen for the AP-1 pathway, RADAR identifies canonical genes from the MAPK and PKC pathways, as well as non-canonical regulators. Thus, our scalable system highlights the benefit and versatility of using genetic circuits in large-scale cell-based screening.

Date: 2021
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DOI: 10.1038/s41467-021-26359-9

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