期刊
MOLECULAR CELL
卷 72, 期 2, 页码 380-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.09.002
关键词
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资金
- Ministry of Science and Technology, China [2014CB943600, 2018YFA0107500]
- National Natural Science Foundation of China [31370858, 81671552]
- Strategic Priority Research Program of Chinese Academy of Sciences [XDB19000000]
- Shanghai Municipal Science and Technology Commission [17ZR449700]
- Department of Science and Technology of Guangdong Province [2016B030229008]
RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention. Conversely, TAM promotes downstream exon inclusion by mutating cytidines into thymines at the polypyrimidine tract. Applying this approach, we genetically restored the open reading frame and dystrophin function of a mutant DMD gene in patient-derived induced pluripotent stem cells (iPSCs). Thus, the CRISPR-guided cytidine deaminase provides a versatile genetic platform to modulate RNA splicing and to correct mutations associated with aberrant splicing in human diseases.
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