X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells
X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells
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DOI：
10.1073/pnas.0712136105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Lee, Jeannie T.
中科院分区：
文献类型：
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作者：
Silva, Susana S.;Rowntree, Rebecca K.;Lee, Jeannie T.
人类胚胎干细胞（hESC）具有产生所有体细胞类型的潜力，作为细胞替代疗法的代理人引起了极大的兴趣。一个潜在的限制是它们在体内的安全性。虽然一些研究集中在对体外基因组稳定性的关注上，但很少有研究分析表观遗传稳定性。在这里，我们使用表观遗传现象的工具，x染色体失活（XCI），研究他们的表观遗传特性。在11个不同的hESC系中，我们发现了高度的可变性。我们发现，与小鼠ESC一样，hESC在培养中诱导分化（I类系）时原则上具有再现XCI的能力。然而，这种能力在少数hESC分离株中可见。许多hESC品系已经进行了XCI （II类和III类）。出乎意料的是，在培养过程中有丢失XIST RNA表达的趋势（III类）。尽管失去了H3-K27三甲基化，III类细胞系的失活X仍然受到转录抑制，如Cot-1 RNA排除所示。我们得出结论，hESC系在体外受到动态表观遗传重编程的影响。鉴于XCI和细胞分化紧密相关，我们考虑了hESC多能性和分化潜力的影响。
With the potential to give rise to all somatic cell types, human embryonic stem cells (hESC) have generated enormous interest as agents of cell replacement therapy. One potential limitation is their safety in vivo. Although several studies have focused on concerns over genomic stability ex vivo, few have analyzed epigenetic stability. Here, we use tools of the epigenetic phenomenon, X-chromosome inactivation (XCI), to investigate their epigenetic properties. Among 11 distinct hESC lines, we find a high degree of variability. We show that, like mouse ESC, hESC in principle have the capacity to recapitulate XCI when induced to differentiate in culture (class I lines). However, this capacity is seen in few hESC isolates. Many hESC lines have already undergone XCI (class II and III). Unexpectedly, there is a tendency to lose XIST RNA expression during culture (class III). Despite losing H3-K27 trimethylation, the inactive X of class III lines remains transcriptionally suppressed, as indicated by Cot-1 RNA exclusion. We conclude that hESC lines are subject to dynamic epigenetic reprogramming ex vivo. Given that XCI and cell differentiation are tightly linked, we consider implications for hESC pluripotency and differentiation potential.