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

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-04
DOI
https://doi.org/10.1038/s41467-024-53735-y
Citations
15
Primary Topic
CRISPR and Genetic Engineering
Type
article
Field-Weighted Citation Impact
3.51

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article

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

Gaurav K. Varshney, Wei Qin, Shaohui Zheng, Ji‐Feng Fei et al.
15 citations
Nature Communications
CRISPR and Genetic Engineering
3.51
article

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

Gaurav K. Varshney, Wei Qin, Shaohui Zheng, Ji‐Feng Fei, Xinxin Xia, Yingxin Zhang, Yan Zhang, Yanmei Liu, Jingjing Zeng, Xin‐hui Yuan, Yu Shi, Juyue Xiao, Hui Ma, Yang Liu
article en
15 citations

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.

Nature CommunicationsVol. 15(1)
South China Normal University (CN), Oklahoma Medical Research Foundation (US), Guangdong Academy of Medical Sciences (CN), Guangdong Provincial People's Hospital (CN), Southern Medical University (CN), South China University of Technology (CN)
Presbyterian Health Foundation, National Natural Science Foundation of China, Wuhan University, Guangdong Provincial People's Hospital
Zero hunger
Openalex Percentile: Top 6%
CRISPR and Genetic Engineering
3.51
DOIOpen Access PDFOpenAlex
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