Mouse genome rewriting and tailoring of three important disease loci

Weimin Zhang, Ilona Golynker, Ran Brosh, Alvaro Fajardo, Yinan Zhu, Aleksandra M. Wudzinska, Raquel Ordoñez, André M. Ribeiro-dos-Santos, Lucia Carrau, Payal Damani-Yokota, Stephen T. Yeung, Camille Khairallah, Antonio Vela Gartner, Noor Chalhoub, Emily Huang, Hannah J. Ashe, Kamal M. Khanna, Matthew T. Maurano, Sang Yong Kim, Benjamin R. tenOever and Jef D. Boeke ()
Additional contact information
Weimin Zhang: NYU Langone Health
Ilona Golynker: NYU Langone Health
Ran Brosh: NYU Langone Health
Alvaro Fajardo: NYU Langone Health
Yinan Zhu: NYU Langone Health
Aleksandra M. Wudzinska: NYU Langone Health
Raquel Ordoñez: NYU Langone Health
André M. Ribeiro-dos-Santos: NYU Langone Health
Lucia Carrau: NYU Langone Health
Payal Damani-Yokota: NYU Langone Health
Stephen T. Yeung: NYU Langone Health
Camille Khairallah: NYU Langone Health
Antonio Vela Gartner: NYU Langone Health
Noor Chalhoub: NYU Langone Health
Emily Huang: NYU Langone Health
Hannah J. Ashe: NYU Langone Health
Kamal M. Khanna: NYU Langone Health
Matthew T. Maurano: NYU Langone Health
Sang Yong Kim: NYU Langone Health
Benjamin R. tenOever: NYU Langone Health
Jef D. Boeke: NYU Langone Health

Nature, 2023, vol. 623, issue 7986, 423-431

Abstract: Abstract Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases1,2. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling. Existing methods set limits on the size and efficiency of DNA delivery, hampering the routine creation of highly informative models that we call genomically rewritten and tailored GEMMs (GREAT-GEMMs). Here we describe ‘mammalian switching antibiotic resistance markers progressively for integration’ (mSwAP-In), a method for efficient genome rewriting in mouse embryonic stem cells. We demonstrate the use of mSwAP-In for iterative genome rewriting of up to 115 kb of a tailored Trp53 locus, as well as for humanization of mice using 116 kb and 180 kb human ACE2 loci. The ACE2 model recapitulated human ACE2 expression patterns and splicing, and notably, presented milder symptoms when challenged with SARS-CoV-2 compared with the existing K18-hACE2 model, thus representing a more human-like model of infection. Finally, we demonstrated serial genome writing by humanizing mouse Tmprss2 biallelically in the ACE2 GREAT-GEMM, highlighting the versatility of mSwAP-In in genome writing.

Date: 2023
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DOI: 10.1038/s41586-023-06675-4

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