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

Patricia Gerdes, Sue Mei Lim, Adam D. Ewing, Michael R. Larcombe, Dorothy Chan, Francisco J. Sanchez-Luque, Lucinda Walker, Alexander L. Carleton, Cini James, Anja S. Knaupp, Patricia E. Carreira, Christian M. Nefzger, Ryan Lister, Sandra R. Richardson (), Jose M. Polo () and Geoffrey J. Faulkner ()
Additional contact information
Patricia Gerdes: Mater Research Institute - University of Queensland
Sue Mei Lim: Monash University
Adam D. Ewing: Mater Research Institute - University of Queensland
Michael R. Larcombe: Monash University
Dorothy Chan: Mater Research Institute - University of Queensland
Francisco J. Sanchez-Luque: Mater Research Institute - University of Queensland
Lucinda Walker: Mater Research Institute - University of Queensland
Alexander L. Carleton: Mater Research Institute - University of Queensland
Cini James: Mater Research Institute - University of Queensland
Anja S. Knaupp: Monash University
Patricia E. Carreira: Mater Research Institute - University of Queensland
Christian M. Nefzger: Monash University
Ryan Lister: The University of Western Australia
Sandra R. Richardson: Mater Research Institute - University of Queensland
Jose M. Polo: Monash University
Geoffrey J. Faulkner: Mater Research Institute - University of Queensland

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35180-x

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