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A synthetic transcription platform for programmable gene expression in mammalian cells

Author(s)
Chen, William CW; Gaidukov, Leonid; Lai, Yong; Wu, Ming-Ru; Cao, Jicong; Gutbrod, Michael J; Choi, Gigi CG; Utomo, Rachel P; Chen, Ying-Chou; Wroblewska, Liliana; Kellis, Manolis; Zhang, Lin; Weiss, Ron; Lu, Timothy K; ... Show more Show less
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Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/
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Abstract
<jats:title>Abstract</jats:title><jats:p>Precise, scalable, and sustainable control of genetic and cellular activities in mammalian cells is key to developing precision therapeutics and smart biomanufacturing. Here we create a highly tunable, modular, versatile CRISPR-based synthetic transcription system for the programmable control of gene expression and cellular phenotypes in mammalian cells. Genetic circuits consisting of well-characterized libraries of guide RNAs, binding motifs of synthetic operators, transcriptional activators, and additional genetic regulatory elements express mammalian genes in a highly predictable and tunable manner. We demonstrate the programmable control of reporter genes episomally and chromosomally, with up to 25-fold more activity than seen with the EF1α promoter, in multiple cell types. We use these circuits to program the secretion of human monoclonal antibodies and to control T-cell effector function marked by interferon-γ production. Antibody titers and interferon-γ concentrations significantly correlate with synthetic promoter strengths, providing a platform for programming gene expression and cellular function in diverse applications.</jats:p>
Date issued
2022
URI
https://hdl.handle.net/1721.1/147941
Department
Massachusetts Institute of Technology. Department of Biological Engineering
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Chen, William CW, Gaidukov, Leonid, Lai, Yong, Wu, Ming-Ru, Cao, Jicong et al. 2022. "A synthetic transcription platform for programmable gene expression in mammalian cells." Nature Communications, 13 (1).
Version: Final published version

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