Dynamic instability of genomic methylation patterns in pluripotent stem cells.
Dynamic instability of genomic methylation patterns in pluripotent stem cells.
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DOI：
10.1186/1756-8935-3-17
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发表时间：
2010-09-24
影响因子：
3.9
通讯作者：
Bestor TH
中科院分区：
文献类型：
--
作者：
Ooi SK;Wolf D;Hartung O;Agarwal S;Daley GQ;Goff SP;Bestor TH
基因组甲基化模式在配子发生期间建立，并通过忠实的维持甲基化在体细胞中延续。以前有迹象表明，基因组甲基化模式可能是不太稳定的胚胎干细胞（ES）比分化的体细胞，但它是不知道是否不同的机制从头和维持甲基化的多能干细胞相比，分化的体细胞。在本文中，我们表明，在小鼠ES细胞中的DNA甲基转移酶调节剂DNMT 3L（DNA甲基转移酶3样）的消融使它们基本上不能从头甲基化的新整合的逆转录病毒DNA。我们还表明，缺乏DNMT 3L的ES细胞在培养中随着时间的推移而失去DNA甲基化，这表明ES细胞中的DNA甲基化是DNA甲基化动态丧失和获得的结果。我们发现，野生型女性ES细胞丢失DNA甲基化的速度比男性ES细胞快得多;这种缺陷不能归因于DNMT 3L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多能干细胞系表现出明显但可变的甲基化丢失，这不能归因于性染色体构成或培养时间。这些数据表明，多能干细胞中的DNA甲基化比分化细胞中的维持甲基化更动态和更容易出错。DNA甲基化需要干细胞中的DNMT 3L，但DNMT 3L在分化的体细胞中不表达。易出错的维持甲基化将向多能干细胞的克隆群体中引入不可预测的表型变异，并且这种变异在培养的雌性细胞中可能更加明显。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。
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. 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. 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.
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影响因子：
64.5
作者：
Okano, M;Bell, DW;Li, E
通讯作者：
Li, E
影响因子：
5.3
作者：
Damelin, Marc;Bestor, Timothy H.
通讯作者：
Bestor, Timothy H.
影响因子：
5.3
作者：
Liang, GG;Chan, MF;Jones, PA
通讯作者：
Jones, PA
影响因子：
56.9
作者：
Humpherys, D;Eggan, K;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
9.2
作者：
Lehnertz, B;Ueda, Y;Peters, AHFM
通讯作者：
Peters, AHFM