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Dynamic instability of genomic methylation patterns in pluripotent stem cells

机译：多能干细胞中基因组甲基化模式的动态不稳定性

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Background Genomic methylation patterns are established during gametogenesis, and perpetuated in somatic cells by faithful maintenance methylation. There have been previous indications that genomic methylation patterns may be less stable in embryonic stem (ES) cells than in differentiated somatic cells, but it is not known whether different mechanisms of de novo and maintenance methylation operate in pluripotent stem cells compared with differentiating somatic cells. Results In this paper, we show that ablation of the DNA methyltransferase regulator DNMT3L (DNA methyltransferase 3-like) in mouse ES cells renders them essentially incapable of de novo methylation of newly integrated retroviral DNA. We also show that ES cells lacking DNMT3L lose DNA methylation over time in culture, suggesting that DNA methylation in ES cells is the result of dynamic loss and gain of DNA methylation. We found that wild-type female ES cells lose DNA methylation at a much faster rate than do male ES cells; this defect could not be attributed to sex-specific differences in expression of DNMT3L or of any DNA methyltransferase. We also found that human ES and induced pluripotent stem cell lines showed marked but variable loss of methylation that could not be attributed to sex chromosome constitution or time in culture. Conclusions These data indicate that DNA methylation in pluripotent stem cells is much more dynamic and error-prone than is maintenance methylation in differentiated cells. DNA methylation requires DNMT3L in stem cells, but DNMT3L is not expressed in differentiating somatic cells. Error-prone maintenance methylation will introduce unpredictable phenotypic variation into clonal populations of pluripotent stem cells, and this variation is likely to be much more pronounced in cultured female cells. This epigenetic variability has obvious negative implications for the clinical applications of stem cells.
机译：背景基因组甲基化模式是在配子发生过程中建立的，并通过忠实的维持甲基化在体细胞中永久存在。以前有迹象表明，胚胎干（ES）细胞中的基因组甲基化模式可能不如分化的体细胞稳定，但是与分化的体细胞相比，在多能干细胞中从头进行和维持甲基化的不同机制是否起作用尚不清楚。结果在本文中，我们显示了小鼠ES细胞中DNA甲基转移酶调节剂DNMT3L（DNA甲基转移酶3样）的消除使它们基本上无法重新整合新整合的逆转录病毒DNA。我们还显示，缺少DNMT3L的ES细胞会随着培养时间的推移而丢失DNA甲基化，这表明ES细胞中的DNA甲基化是动态损失和DNA甲基化获得的结果。我们发现，野生型雌性ES细胞的DNA甲基化损失速率比雄性ES细胞快得多。此缺陷不能归因于DNMT3L或任何DNA甲基转移酶表达的性别特异性差异。我们还发现，人类胚胎干细胞和诱导的多能干细胞系显示出明显但可变的甲基化损失，这不能归因于性染色体的构成或培养时间。结论这些数据表明，与分化细胞中维持甲基化相比，多能干细胞中的DNA甲基化具有更大的动态性和错误倾向。 DNA甲基化在干细胞中需要DNMT3L，但是DNMT3L在分化的体细胞中不表达。容易出错的维持甲基化将在多能干细胞的克隆种群中引入不可预测的表型变异，这种变异在培养的雌性细胞中可能更为明显。这种表观遗传变异性对干细胞的临床应用具有明显的负面影响。

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