The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell Stem Cell. 2012 May 4;10(5):595-609. doi: 10.1016/j.stem.2012.02.014.
Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an "erosion" of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease.
尽管不同的人诱导多能干细胞（hiPSC）系可以表现出相当大的表观遗传变异，但尚不清楚这种可变性是否会影响它们在疾病建模中的应用。在这里，我们表明，尽管低传代的女性 hiPSC 保留了其来源于的体细胞的失活 X 染色体，但随着时间的推移在培养中，它们会经历 X 染色体失活（XCI）的“侵蚀”。这种 XCI 的侵蚀的特征是 XIST 表达和 H3-K27-三甲基化焦点的丧失，以及失活 X 上的基因的转录去抑制，这些基因不能通过分化或进一步重编程逆转。我们特别证明，XCI 的侵蚀对使用女性 hiPSC 进行 Lesch-Nyhan 综合征的建模有重大影响。然而，我们发现，大多数受 XCI 调控的基因都被这种 XCI 的侵蚀所解除抑制，这表明在选择 hiPSC 系进行任何疾病建模时，都应该考虑到这一点。
