Cultured pluripotent cells accumulate detrimental chromatin alterations, including DNA methylation changes at imprinted genes known as loss of imprinting (LOI). Although the occurrence of LOI is considered a stochastic phenomenon, here we document a genetic determinant that segregates mouse pluripotent cells into stable and unstable cell lines. Unstable lines exhibit hypermethylation at Dlk1-Dio3 and other imprinted loci, in addition to impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and loss of developmental potential. Susceptibility to LOI greatly differs between commonly used mouse strains, which we use to map a causal region on chromosome 13 with quantitative trait locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific chromatin 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.

培养的多能细胞会积聚有害的染色质改变，包括在印记基因上的DNA甲基化改变，称为印记丢失（LOI）。尽管LOI的发生被认为是随机现象，但在这里我们记录了一个遗传决定因素，它将小鼠多能细胞分离成稳定和不稳定的细胞系。不稳定的品系在Dlk1-Dio3处表现出高甲基化和其他印迹基因座，以及受损的发展潜力。抗坏血酸刺激脱甲基酶可防止LOI和发育潜能的丧失。LOI的易感性在常用的小鼠品系之间存在很大差异，我们使用数量性状基因座（QTL）分析来绘制13号染色体上的因果区域。我们的观察结果确定了多能细胞中基因座特异性染色质异常的强大遗传决定因素，并提供了一种非侵入性的方式来抑制它们。这突出了考虑遗传因素与培养条件一起确保生物医学应用的多能细胞质量的重要性。