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A Synthetic Transcription Platform for Programmable Gene Expression in Mammalian Cells

By William CW Chen, Leonid Gaidukov, Ming-Ru Wu, Jicong Cao, Gigi C.G. Choi, Rachel P. Utomo, Ying-Chou Chen, Liliana Wroblewska, Lin Zhang, Ron Weiss, Timothy K Lu

Posted 11 Dec 2020
bioRxiv DOI: 10.1101/2020.12.11.420000

Precise, scalable, and sustainable control of genetic and cellular activities in mammalian cells is key to developing precision therapeutics and smart biomanufacturing. We created 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 expressed mammalian genes in a highly predictable and tunable manner. We demonstrated the programmable control of reporter genes episomally and chromosomally, with up to 25-fold more EF1[alpha]; promoter activity, in multiple cell types. We used these circuits to program secretion of human monoclonal antibodies and to control T cell effector function marked by interferon-[gamma] production. Antibody titers and interferon-[gamma]; concentrations were significantly correlated with synthetic promoter strengths, providing a platform for programming gene expression and cellular function for biological, biomanufacturing, and biomedical applications.

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