Título:
Mouse genome rewriting and tailoring of three important disease loci
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Autor:
Zhang, Weimin
Golynker, Ilona
Fajardo Rossi, Álvaro
Golynker, Ilona
Fajardo Rossi, Álvaro
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Tipo de documento:
Artículo
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Palabras clave:
Mouse genome
Non-coding regulatory genome sequences
mSwAP-In
ACE2 model
Non-coding regulatory genome sequences
mSwAP-In
ACE2 model
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Año de publicación:
2023
Contenido:
Resumen:
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 efciency 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 efcient 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.
Descripción:
Artículo escrito por 21 autores
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Editorial:
Nature
EN:
Nature, 2023, 623(7986): 423–431.
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Citación:
Zhang, W, Golynker, I y Fajardo Rossi, Á [y otros autores]. "Mouse genome rewriting and tailoring of three important disease loci". Nature. [en línea] 2023, 623(7986): 423–431. 33 h. DOI: 10.1038/s41586-023-06675-4.
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1476-4687
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Licencia:
Licencia Creative Commons Atribución (CC - By 4.0)
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| Ficheros | Descripción | Tamaño | Formato | ||
|---|---|---|---|---|---|
| 10.1038.s41586-023-06675-4.pdf | — | 7.35 MB | Adobe PDF |