Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53735-y |
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| _version_ | 1850061885328588800 |
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| author | 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 Yanmei Liu |
| author_facet | 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 Yanmei Liu |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6a182ad0fa8c4a7598f100335ea9385a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6a182ad0fa8c4a7598f100335ea9385a2025-08-20T02:50:04ZengNature PortfolioNature Communications2041-17232024-11-0115111010.1038/s41467-024-53735-yCytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafishYu Zhang0Yang Liu1Wei Qin2Shaohui Zheng3Jiawang Xiao4Xinxin Xia5Xuanyao Yuan6Jingjing Zeng7Yu Shi8Yan Zhang9Hui Ma10Gaurav K. Varshney11Ji-Feng Fei12Yanmei Liu13Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityGenes & Human Disease Research Program, Oklahoma Medical Research FoundationKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityDepartment of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityGenes & Human Disease Research Program, Oklahoma Medical Research FoundationDepartment of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityKey Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal UniversityAbstract 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.https://doi.org/10.1038/s41467-024-53735-y |
| spellingShingle | 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 Yanmei Liu Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish Nature Communications |
| title | Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish |
| title_full | Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish |
| title_fullStr | Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish |
| title_full_unstemmed | Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish |
| title_short | Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish |
| title_sort | cytosine base editors with increased pam and deaminase motif flexibility for gene editing in zebrafish |
| url | https://doi.org/10.1038/s41467-024-53735-y |
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