Precise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system

Chenrui Qin, Yanhui Xiang, Jie Liu, Ruilin Zhang, Ziming Liu, Tingting Li, Zhi Sun, Xiaoyi Ouyang, Yeqing Zong, Haoqian M. Zhang, Qi Ouyang, Long Qian () and Chunbo Lou ()
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Chenrui Qin: Peking University
Yanhui Xiang: Chinese Academy of Sciences
Jie Liu: Chinese Academy of Sciences
Ruilin Zhang: Peking University
Ziming Liu: Chinese Academy of Sciences
Tingting Li: Chinese Academy of Sciences
Zhi Sun: University of Chinese Academy of Science
Xiaoyi Ouyang: Peking University
Yeqing Zong: Bluepha Co., Ltd
Haoqian M. Zhang: Bluepha Co., Ltd
Qi Ouyang: Peking University
Long Qian: Peking University
Chunbo Lou: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Context-dependency of mammalian transcriptional elements has hindered the quantitative investigation of multigene expression stoichiometry and its biological functions. Here, we describe a host- and local DNA context-independent transcription system to gradually fine-tune single and multiple gene expression with predictable stoichiometries. The mammalian transcription system is composed of a library of modular and programmable promoters from bacteriophage and its cognate RNA polymerase (RNAP) fused to a capping enzyme. The relative expression of single genes is quantitatively determined by the relative binding affinity of the RNAP to the promoters, while multigene expression stoichiometry is predicted by a simple biochemical model with resource competition. We use these programmable and modular promoters to predictably tune the expression of three components of an influenza A virus-like particle (VLP). Optimized stoichiometry leads to a 2-fold yield of intact VLP complexes. The host-independent orthogonal transcription system provides a platform for dose-dependent control of multiple protein expression which may be applied for advanced vaccine engineering, cell-fate programming and other therapeutic applications.

Date: 2023
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DOI: 10.1038/s41467-023-37244-y

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