Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells Journal Article
| Authors: | Parikh, C.; Glenn, R. A.; Shi, Y.; Chatterjee, K.; Kasliwal, K.; Swanzey, E. E.; Singer, S.; Do, S. C.; Zhan, Y.; Furuta, Y.; Tahiliani, M.; Apostolou, E.; Polyzos, A.; Koche, R.; Mezey, J. G.; Vierbuchen, T.; Stadtfeld, M. |
| Article Title: | Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naive pluripotent stem cells |
| Abstract: | Naive pluripotent stem cells (nPSCs) frequently undergo pathological loss of DNA methylation at imprinted gene loci, posing a hurdle for biomedical applications and underscoring the need to identify underlying causes. We show that nPSCs from inbred mouse strains exhibit strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming and upon exposure to a mitogen-activated protein kinase (MAPK) inhibitor, a common approach to maintain naive pluripotency. Analysis of genetically diverse nPSCs from the Diversity Outbred (DO) stock confirms the impact of genetic variation on epigenome stability, which we leverage to identify trans-acting quantitative trait loci (QTLs) that modulate DNA methylation levels at specific targets or genome-wide. Analysis of multi-target QTLs on chromosomes 4 and 17 suggests candidate transcriptional regulators contributing to DNA methylation maintenance in nPSCs. We propose that genetic variants represent biomarkers to identify pluripotent cell lines with desirable properties and may allow the targeted engineering of nPSCs with stable epigenomes. © 2025 The Author(s) |
| Keywords: | controlled study; genetics; nonhuman; animal cell; mouse; animal; cytology; metabolism; animals; mice; gene locus; genetic variability; genetic variation; dna methylation; haplotype; regulatory mechanism; transcription regulation; messenger rna; histone methyltransferase; epigenesis, genetic; genetic susceptibility; histone h3; pluripotent stem cell; pluripotent stem cells; dna methyltransferase; genetic epigenesis; genome imprinting; genomic imprinting; chromosome 17; quantitative trait locus; quantitative trait loci; nuclear reprogramming; in vitro fertilization; chromosome 4; quantitative trait locus mapping; epigenome; cellular reprogramming; lod score; male; female; article; inbred mouse strain; genetic background; naive pluripotency; expression quantitative trait locus; dna methylation age; mirdametinib; diversity outbred mice; epigenetic instability; qtl mapping; outbred mouse strain |
| Journal Title: | Stem Cell Reports |
| Volume: | 20 |
| Issue: | 4 |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press |
| Date Published: | 2025-04-08 |
| Start Page: | 102450 |
| Language: | English |
| DOI: | 10.1016/j.stemcr.2025.102450 |
| PUBMED: | 40086447 |
| PROVIDER: | scopus |
| PMCID: | PMC12069886 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is T. Vierbuchen -- Source: Scopus |
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