DNA Methylation Dynamics in Human Induced Pluripotent Stem Cells over Time
DNA Methylation Dynamics in Human Induced Pluripotent Stem Cells over Time
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DOI：
10.1371/journal.pgen.1002085
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发表时间：
2011-05-01
期刊：
影响因子：
4.5
通讯作者：
Umezawa, Akihiro
中科院分区：
文献类型：
--
作者：
Nishino, Koichiro;Toyoda, Masashi;Umezawa, Akihiro
表观遗传重编程是诱导多能干细胞 (iPSC) 生成的关键事件。在这里，我们确定了源自五种不同细胞类型（人子宫内膜、胎盘动脉内皮、羊膜、胎肺成纤维细胞和月经血细胞）的 22 种人类 iPSC 系和 5 种人类胚胎干细胞 (ESC) 系的 DNA 甲基化谱，并对 iPSC 中的异常甲基化位点进行了长达 42 周的跟踪。 iPSC 与 ESC 表现出明显的表观遗传差异，这是由早期传代时的异常甲基化引起的。在 iPSC 重编程过程中，检测到随机异常甲基化的多次出现和消失。 iPSC 的连续传代减少了 iPSC 和 ESC 之间的差异，这意味着 iPSC 失去了从亲代细胞继承的特征，并随着时间的推移适应与 ESC 非常相似的特征。人类iPSC通过不断以从头方式出现的异常高甲基化事件的“聚合”而逐渐重编程。这种iPS重编程包括随机从头甲基化和在适合ESC的环境中选择/固定甲基化。总而言之，随机甲基化和聚合是iPSC长期重编程为ESC的驱动力。
Epigenetic reprogramming is a critical event in the generation of induced pluripotent stem cells (iPSCs). Here, we determined the DNA methylation profiles of 22 human iPSC lines derived from five different cell types (human endometrium, placental artery endothelium, amnion, fetal lung fibroblast, and menstrual blood cell) and five human embryonic stem cell (ESC) lines, and we followed the aberrant methylation sites in iPSCs for up to 42 weeks. The iPSCs exhibited distinct epigenetic differences from ESCs, which were caused by aberrant methylation at early passages. Multiple appearances and then disappearances of random aberrant methylation were detected throughout iPSC reprogramming. Continuous passaging of the iPSCs diminished the differences between iPSCs and ESCs, implying that iPSCs lose the characteristics inherited from the parent cells and adapt to very closely resemble ESCs over time. Human iPSCs were gradually reprogrammed through the "convergence'' of aberrant hyper-methylation events that continuously appeared in a de novo manner. This iPS reprogramming consisted of stochastic de novo methylation and selection/fixation of methylation in an environment suitable for ESCs. Taken together, random methylation and convergence are driving forces for long-term reprogramming of iPSCs to ESCs.