A Susceptibility Locus on Chromosome 13 Profoundly Impacts the Stability of Genomic Imprinting in Mouse Pluripotent Stem Cells

• DOI: 10.1016/j.celrep.2020.02.073
• Publication Date: 2020-03-17T14:39:33Z
• Authors: Emily Swanzey; Thomas F. McNamara; Effie Apostolou; Mamta Tahiliani; Matthias Stadtfeld
• Keywords: Pluripotent Stem Cells; 0301 basic medicine; QH301-705.5; Calcium-Binding Proteins; Quantitative Trait Loci; Embryonic Development; Mouse Embryonic Stem Cells; Ascorbic Acid; DNA Methylation; Chromosomes, Mammalian; Cell Line; Epigenesis, Genetic; Mice, Inbred C57BL; Genomic Imprinting; Mice; 03 medical and health sciences; Genetic Loci; Animals; Biology (General)

SummaryCultured pluripotent cells accumulate detrimental epigenetic alterations, including DNA methylation changes at imprinted genes known as loss-of-imprinting (LOI). Despite the substantial biomedical relevance of this phenomenon, the molecular cause of this epigenetic instability in pluripotent cells remains unknown. While the occurrence of LOI is generally considered a stochastic phenomenon, here we document a strong genetic determinant that segregates mouse pluripotent cells into epigenetically stable and unstable cell lines. Unstable lines exhibit hypermethylation atDlk1-Dio3and select other imprinted loci, which is associated with impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and can preserve developmental potential. Susceptibility to LOI greatly differs between commonly used mouse strains, which we utilize to map a causal region on chromosome 13 with Quantitative Trait Locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific epigenetic abnormalities in pluripotent cells and provide a non-invasive way to suppress them. This highlights the importance of considering genetics in conjunction with culture conditions for assuring the quality of pluripotent cells for biomedical applications.