Engineered minimal type I CRISPR-Cas system for transcriptional activation and base editing in human cells

Jing Guo, Luyao Gong (), Haiying Yu, Ming Li, Qiaohui An, Zhenquan Liu, Shuru Fan, Changjialian Yang, Dahe Zhao, Jing Han and Hua Xiang ()
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Jing Guo: Chinese Academy of Sciences
Luyao Gong: Chinese Academy of Sciences
Haiying Yu: Chinese Academy of Sciences
Ming Li: Chinese Academy of Sciences
Qiaohui An: Chinese Academy of Sciences
Zhenquan Liu: Chinese Academy of Sciences
Shuru Fan: Chinese Academy of Sciences
Changjialian Yang: Chinese Academy of Sciences
Dahe Zhao: Chinese Academy of Sciences
Jing Han: Chinese Academy of Sciences
Hua Xiang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Type I CRISPR-Cas systems are widespread and have exhibited high versatility and efficiency in genome editing and gene regulation in prokaryotes. However, due to the multi-subunit composition and large size, their application in eukaryotes has not been thoroughly investigated. Here, we demonstrate that the type I-F2 Cascade, the most compact among type I systems, with a total gene size smaller than that of SpCas9, can be developed for transcriptional activation in human cells. The efficiency of the engineered I-F2 tool can match or surpass that of dCas9. Additionally, we create a base editor using the I-F2 Cascade, which induces a considerably wide editing window (~30 nt) with a bimodal distribution. It can expand targetable sites, which is useful for disrupting functional sequences and genetic screening. This research underscores the application of compact type I systems in eukaryotes, particularly in the development of a base editor with a wide editing window.

Date: 2024
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DOI: 10.1038/s41467-024-51695-x

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