Kevin Eggan2014-02-27 12:11 PM

减少计量补偿影响人类iPSC疾病模型。Erosion of dosage compensation impacts human iPSC disease modeling.

论文摘要

虽然不同人类诱导多能干细胞(hiPSC)线能展示出显著表观遗传变异,但我们仍不清楚该变动是否会影响它对疾病模型的效用。在这里,我们表明虽然低传递的女性iPS细胞保存了源自体细胞的失活X染色体,随着培育时间的推移,他们经历了X染色体失活( XCI )的“侵蚀”。XCI侵蚀的特征是XIST表达的损失,H3 - K27 -三甲基中心的丢失以及无法通过分化或更深入再编辑而得到逆转的失活X上的基因的转录去抑制。我们明确表明XCI侵蚀会对使用女性iPS细胞建模莱 - 尼综合征产生显著影响。然而,我们发现大多数受XCI支配的基因都通过这种XCI侵蚀实现了去抑制。这表明我们在选择hiPSC线来建模任何疾病时都应将它重点考虑在内。


Abstract 

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.

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Kevin Eggan

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