Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells.

Autor: Gerdes P; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Lim SM; Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia.; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, 3800, Australia.; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, 3800, Australia., Ewing AD; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Larcombe MR; Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia.; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, 3800, Australia.; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, 3800, Australia., Chan D; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Sanchez-Luque FJ; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia.; GENYO. Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research, PTS, Granada, 18016, Spain., Walker L; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Carleton AL; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., James C; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Knaupp AS; Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia.; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, 3800, Australia.; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, 3800, Australia., Carreira PE; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia., Nefzger CM; Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia.; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, 3800, Australia.; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, 3800, Australia., Lister R; Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA, 6009, Australia.; Harry Perkins Institute of Medical Research, Perth, WA, 6009, Australia., Richardson SR; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia. sandra.richardson@mater.uq.edu.au., Polo JM; Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC, 3800, Australia. jose.polo@monash.edu.; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, 3800, Australia. jose.polo@monash.edu.; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, 3800, Australia. jose.polo@monash.edu.; Adelaide Centre for Epigenetics and The South Australian Immunogenomics Cancer Institute, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia. jose.polo@monash.edu., Faulkner GJ; Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia. faulknergj@gmail.com.; Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia. faulknergj@gmail.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Dec 03; Vol. 13 (1), pp. 7470. Date of Electronic Publication: 2022 Dec 03.
DOI: 10.1038/s41467-022-35180-x
Abstrakt: Induced pluripotent stem cells (iPSCs) can in principle differentiate into any cell of the body, and have revolutionized biomedical research and regenerative medicine. Unlike their human counterparts, mouse iPSCs (miPSCs) are reported to silence transposable elements and prevent transposable element-mediated mutagenesis. Here we apply short-read or Oxford Nanopore Technologies long-read genome sequencing to 38 bulk miPSC lines reprogrammed from 10 parental cell types, and 18 single-cell miPSC clones. While single nucleotide variants and structural variants restricted to miPSCs are rare, we find 83 de novo transposable element insertions, including examples intronic to Brca1 and Dmd. LINE-1 retrotransposons are profoundly hypomethylated in miPSCs, beyond other transposable elements and the genome overall, and harbor alternative protein-coding gene promoters. We show that treatment with the LINE-1 inhibitor lamivudine does not hinder reprogramming and efficiently blocks endogenous retrotransposition, as detected by long-read genome sequencing. These experiments reveal the complete spectrum and potential significance of mutations acquired by miPSCs.
(© 2022. The Author(s).)
Databáze: MEDLINE
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