Large-Scale Analysis of Loss of Imprinting in Human Pluripotent Stem Cells
Large-Scale Analysis of Loss of Imprinting in Human Pluripotent Stem Cells
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DOI：
10.1016/j.celrep.2017.04.020
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发表时间：
2017-05-02
期刊：
影响因子：
8.8
通讯作者：
Benvenisty, Nissim
中科院分区：
文献类型：
--
作者：
Bar, Shiran;Schachter, Maya;Benvenisty, Nissim
父母特异性的单等位基因的印记基因的表达是由DNA甲基化标记，是建立在种系差异控制。这些标记的扰动导致印记丢失（LOI），这与发育障碍和恶性肿瘤相关，并且还可能阻碍人多能干细胞（hPSC）的应用。先前对hPSC中LOI的研究是在相对少量的细胞系上进行的，这通常导致关于印迹稳定性的相互矛盾的结论。在这里，我们通过对来自270多个hPSC样品的等位基因特异性RNA-seq数据进行大规模分析，绘制了hPSC中LOI的景观。我们发现，与胚胎干细胞相比，重编程的hPSC获得更高水平的LOI，并且LOI可以预先存在于其起源的体细胞中。此外，不同的印记基因相对于LOI发生率不同，令人惊讶地揭示了那些父系控制的基因更容易被破坏。我们的研究结果强调了检查hPSC印迹状态的重要性。
The parent-specific monoallelic expression of imprinted genes is controlled by DNA methylation marks that are established differentially in the germline. Perturbation of these marks leads to loss of imprinting (LOI), which is associated with developmental disorders and malignancy and may also obstruct applications of human pluripotent stem cells (hPSCs). Previous studies of LOI in hPSCs were performed on relatively small numbers of cell lines, often leading to conflicting conclusions regarding imprinting stability. Here, we chart the landscape of LOI in hPSCs by applying a large-scale analysis of allele-specific RNA-seq data from more than 270 hPSC samples. We show that reprogrammed hPSCs acquire higher levels of LOI compared with embryonic stem cells and that LOI can pre-exist in their somatic cells of origin. Furthermore, different imprinted genes vary with respect to LOI incidence, surprisingly revealing that those controlled paternally are more prone to disruption. Our findings emphasize the importance of inspecting the imprinting status of hPSCs.