Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells
(2022) In Nature Communications 13(1).- 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... (More)
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.
(Less)
- author
- publishing date
- 2022-12-03
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Mice, Animals, Induced Pluripotent Stem Cells, Retroelements/genetics, DNA Transposable Elements/genetics, Mutation, Long Interspersed Nucleotide Elements/genetics
- in
- Nature Communications
- volume
- 13
- issue
- 1
- article number
- 7470
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:36463236
- scopus:85143119028
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-022-35180-x
- language
- English
- LU publication?
- no
- additional info
- © 2022. The Author(s).
- id
- f5fe6ef0-3ce1-4d5a-af97-fde38c3893a8
- date added to LUP
- 2024-06-10 15:13:57
- date last changed
- 2024-06-11 04:01:15
@article{f5fe6ef0-3ce1-4d5a-af97-fde38c3893a8, abstract = {{<p>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.</p>}}, author = {{Gerdes, Patricia and Lim, Sue Mei and Ewing, Adam D and Larcombe, Michael R and Chan, Dorothy and Sanchez-Luque, Francisco J and Walker, Lucinda and Carleton, Alexander L and James, Cini and Knaupp, Anja S and Carreira, Patricia E and Nefzger, Christian M and Lister, Ryan and Richardson, Sandra R and Polo, Jose M and Faulkner, Geoffrey J}}, issn = {{2041-1723}}, keywords = {{Humans; Mice; Animals; Induced Pluripotent Stem Cells; Retroelements/genetics; DNA Transposable Elements/genetics; Mutation; Long Interspersed Nucleotide Elements/genetics}}, language = {{eng}}, month = {{12}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells}}, url = {{http://dx.doi.org/10.1038/s41467-022-35180-x}}, doi = {{10.1038/s41467-022-35180-x}}, volume = {{13}}, year = {{2022}}, }