Adenine base editor–mediated splicing remodeling activates noncanonical splice sites

• DOI: 10.1016/j.jbc.2023.105442
• Publication Date: 2023-11-09T08:18:11Z
• Authors: Yuanyuan Liu; Qing Li; Tong Yan; Haoran Chen; Jiahua Wang; Yingyi Wang; Yeqin Yang; Lue Xiang; Zailong Chi; Kaiqun Ren; Bin Lin; Ge Lin; Jinsong Li; Yong Liu; Feng Gu
• Keywords: splice

Adenine base editors (ABEs) are genome-editing tools that have been harnessed to introduce precise A•T G•C conversion. The discovery of split genes revealed all introns contain two highly conserved dinucleotides, canonical "AG" (acceptor) and "GT" (donor) splice sites. ABE can directly edit acceptor sites the adenine (A) base, leading aberrant gene splicing, which may be further adopted remodel splicing. However, spliced isoforms triggered with not well explored. To address it, we initially generated a cell line harboring C-terminal enhanced GFP (eGFP)-tagged β-actin (ACTB), in eGFP signal track endogenous expression. Expectedly, after editing sites, observed dramatical decrease percentage eGFP-positive cells generation splicing products noncanonical site. Furthermore, manipulated Peroxidasin mouse embryos ABE, was activated successfully generating disease model anophthalmia severely malformed microphthalmia. Collectively, demonstrate ABE-mediated remodeling activate manipulate human genomes, will facilitate investigation basic translational medicine studies.