Ludwig Guy, Nejman Deborah, Hecht Merav, Orlanski Shari, Abu-Remaileh Monther, Yanuka Ofra, Sandler Oded, Marx Amichai, Roberts Douglas, Benvenisty Nissim, Bergman Yehudit, Mendelsohn Monica, Cedar Howard
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
PLoS One. 2014 May 22;9(5):e96090. doi: 10.1371/journal.pone.0096090. eCollection 2014.
Both mouse and human embryonic stem cells can be differentiated in vitro to produce a variety of somatic cell types. Using a new developmental tracing approach, we show that these cells are subject to massive aberrant CpG island de novo methylation that is exacerbated by differentiation in vitro. Bioinformatics analysis indicates that there are two distinct forms of abnormal de novo methylation, global as opposed to targeted, and in each case the resulting pattern is determined by molecular rules correlated with local pre-existing histone modification profiles. Since much of the abnormal methylation generated in vitro appears to be stably maintained, this modification may inhibit normal differentiation and could predispose to cancer if cells are used for replacement therapy. Excess CpG island methylation is also observed in normal placenta, suggesting that this process may be governed by an inherent program.
小鼠和人类胚胎干细胞均可在体外分化产生多种体细胞类型。利用一种新的发育追踪方法，我们发现这些细胞会发生大量异常的从头CpG岛甲基化，且体外分化会加剧这种现象。生物信息学分析表明，存在两种不同形式的异常从头甲基化，即全局型与靶向型，并且在每种情况下，所产生的模式均由与局部预先存在的组蛋白修饰谱相关的分子规则决定。由于体外产生的许多异常甲基化似乎能稳定维持，这种修饰可能会抑制正常分化，并且如果将这些细胞用于替代疗法，可能会引发癌症。在正常胎盘中也观察到了过量的CpG岛甲基化，这表明该过程可能受固有程序调控。
