Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells

Youjun Wu, Aaron Zhong, Mega Sidharta, Tae Wan Kim, Bernny Ramirez, Benjamin Persily, Lorenz Studer () and Ting Zhou ()
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Youjun Wu: 1275 York Avenue
Aaron Zhong: 1275 York Avenue
Mega Sidharta: 1275 York Avenue
Tae Wan Kim: 1275 York Avenue
Bernny Ramirez: 1275 York Avenue
Benjamin Persily: 1275 York Avenue
Lorenz Studer: 1275 York Avenue
Ting Zhou: 1275 York Avenue

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small insertions or deletions at a specific genomic locus. Here, we systematically compare a panel of prime editing conditions in hPSCs and generate a potent prime editor, “PE-Plus”, through co-inhibition of mismatch repair and p53-mediated cellular stress responses. We further establish an inducible prime editing platform in hPSCs by incorporating the PE-Plus into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells. By evaluating disease-associated mutations, we show that this platform allows efficient creation of both monoallelic and biallelic disease-relevant mutations in hPSCs. In addition, this platform enables the efficient introduction of single or multiple edits in one step, demonstrating potential for multiplex editing. Our method presents an efficient and controllable multiplex prime editing tool in hPSCs and their differentiated progeny.

Date: 2024
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DOI: 10.1038/s41467-024-55104-1

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