Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish

Yu Zhang, Yang Liu, Wei Qin, Shaohui Zheng, Jiawang Xiao, Xinxin Xia, Xuanyao Yuan, Jingjing Zeng, Yu Shi, Yan Zhang, Hui Ma, Gaurav K. Varshney (), Ji-Feng Fei () and Yanmei Liu ()
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Yu Zhang: South China Normal University
Yang Liu: South China Normal University
Wei Qin: Oklahoma Medical Research Foundation
Shaohui Zheng: South China Normal University
Jiawang Xiao: South China Normal University
Xinxin Xia: South China Normal University
Xuanyao Yuan: South China Normal University
Jingjing Zeng: South China Normal University
Yu Shi: South China Normal University
Yan Zhang: South China Normal University
Hui Ma: Southern Medical University
Gaurav K. Varshney: Oklahoma Medical Research Foundation
Ji-Feng Fei: Southern Medical University
Yanmei Liu: South China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Cytosine base editing is a powerful tool for making precise single nucleotide changes in cells and model organisms like zebrafish, which are valuable for studying human diseases. However, current base editors struggle to edit cytosines in certain DNA contexts, particularly those with GC and CC pairs, limiting their use in modelling disease-related mutations. Here we show the development of zevoCDA1, an optimized cytosine base editor for zebrafish that improves editing efficiency across various DNA contexts and reduces restrictions imposed by the protospacer adjacent motif. We also create zevoCDA1-198, a more precise editor with a narrower editing window of five nucleotides, minimizing off-target effects. Using these advanced tools, we successfully generate zebrafish models of diseases that were previously challenging to create due to sequence limitations. This work enhances the ability to introduce human pathogenic mutations in zebrafish, broadening the scope for genomic research with improved precision and efficiency.

Date: 2024
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DOI: 10.1038/s41467-024-53735-y

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