Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/137152
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Type: | Journal article |
Title: | Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells. |
Author: | Gerdes, P. Lim, S.M. Ewing, A.D. Larcombe, M.R. Chan, D. Sanchez-Luque, F.J. Walker, L. Carleton, A.L. James, C. Knaupp, A.S. Carreira, P.E. Nefzger, C.M. Lister, R. Richardson, S.R. Polo, J.M. Faulkner, G.J. |
Citation: | Nature Communications, 2022; 13(1) |
Publisher: | Springer Science and Business Media LLC |
Issue Date: | 2022 |
ISSN: | 2041-1723 2041-1723 |
Statement of Responsibility: | Patricia Gerdes, SueMei Lim, AdamD. 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, Geoffrey J. Faulkner |
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. |
Keywords: | Animals Humans Mice DNA Transposable Elements Retroelements Long Interspersed Nucleotide Elements Mutation Induced Pluripotent Stem Cells |
Rights: | © The Author(s) 2022 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. |
DOI: | 10.1038/s41467-022-35180-x |
Grant ID: | http://purl.org/au-research/grants/arc/DE150101117 http://purl.org/au-research/grants/nhmrc/GNT1051117 http://purl.org/au-research/grants/arc/FT180100674 http://purl.org/au-research/grants/nhmrc/GNT1178460 http://purl.org/au-research/grants/nhmrc/GNT1173476 http://purl.org/au-research/grants/nhmrc/GNT1173711 http://purl.org/au-research/grants/nhmrc/GNT1106206 http://purl.org/au-research/grants/nhmrc/GNT1125645 http://purl.org/au-research/grants/nhmrc/GNT1126393 http://purl.org/au-research/grants/nhmrc/GNT1138795 |
Published version: | http://dx.doi.org/10.1038/s41467-022-35180-x |
Appears in Collections: | Molecular and Biomedical Science publications |
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hdl_137152.pdf | Published version | 2.65 MB | Adobe PDF | View/Open |
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