A Susceptibility Locus on Chromosome 13 Profoundly Impacts the Stability of Genomic Imprinting in Mouse Pluripotent Stem Cells.
A Susceptibility Locus on Chromosome 13 Profoundly Impacts the Stability of Genomic Imprinting in Mouse Pluripotent Stem Cells.
复制标题
13 号染色体上的易感位点深刻影响小鼠多能干细胞基因组印记的稳定性。
DOI：
10.1016/j.celrep.2020.02.073
复制
发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Stadtfeld,Matthias
中科院分区：
文献类型：
--
作者：
Swanzey,Emily;McNamara,ThomasF;Apostolou,Effie;Tahiliani,Mamta;Stadtfeld,Matthias
培养的多能细胞积累有害的染色质改变，包括被称为印记丢失（LOI）的印记基因的DNA甲基化变化。虽然LOI的发生被认为是一种随机现象，在这里，我们记录了一个遗传决定因素，小鼠多能细胞分离成稳定和不稳定的细胞系。不稳定品系表现出Dlk 1-Dio 3和其他印迹位点的高甲基化，此外发育潜力受损。抗坏血酸对脱甲基酶的刺激可防止LOI和发育潜力的丧失。对LOI的敏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）分析来定位13号染色体上的因果区域。我们的观察确定了多能细胞中基因座特异性染色质异常的强遗传决定因素，并提供了一种非侵入性的抑制方法。这突出了将遗传学与培养条件结合起来考虑的重要性，以确保用于生物医学应用的多能细胞的质量。
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 atDlk1-Dio3and 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.