Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells
Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells
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DOI：
10.1073/pnas.1202352109
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发表时间：
2012-10-02
影响因子：
11.1
通讯作者：
Izpisua Belmonte, Juan Carlos
中科院分区：
文献类型：
--
作者：
Ruiz, Sergio;Diep, Dinh;Izpisua Belmonte, Juan Carlos
通过表达特异性转录因子产生人诱导多能干细胞（hiPSC）取决于成功的表观遗传重编程为多能状态。虽然hiPSC和人胚胎干细胞（hESC）显示出相似的表观基因组，但最近的报告表明，来自体细胞起源类型的特定表观遗传标记和hiPSC中的异常甲基化模式持续存在。然而，仍然不清楚使用不同的体细胞来源，包括重编程期间可变水平的选择压力，是否会影响hiPSC中的表观遗传畸变水平。在这项工作中，我们表征了17个hiPSC系的表观基因组完整性，这些hiPSC系来源于具有不同重编程效率的六种不同细胞类型。我们证明了表观遗传畸变是hiPSC状态的一般特征，并且独立于体细胞来源。有趣的是，我们观察到体细胞系的重编程效率与获得多能性所需的甲基化变化量呈负相关。此外，我们确定hiPSC中的共有和品系特异性表观遗传畸变可以直接转化为多能和分化状态下基因表达的变化。值得注意的是，我们对来自多种细胞类型来源的不同hiPSC系的分析允许我们鉴定由9个异常甲基化基因组成的重编程特异性表观遗传特征，其能够分离hESC和hiPSC系，而不管体细胞来源或分化状态如何。
Generation of human induced pluripotent stem cells (hiPSCs) by the expression of specific transcription factors depends on successful epigenetic reprogramming to a pluripotent state. Although hiPSCs and human embryonic stemcells (hESCs) display a similar epigenome, recent reports demonstrated the persistence of specific epigenetic marks from the somatic cell type of origin and aberrant methylation patterns in hiPSCs. However, it remains unknown whether the use of different somatic cell sources, encompassing variable levels of selection pressure during reprogramming, influences the level of epigenetic aberrations in hiPSCs. In this work, we characterized the epigenomic integrity of 17 hiPSC lines derived from six different cell types with varied reprogramming efficiencies. We demonstrate that epigenetic aberrations are a general feature of the hiPSC state and are independent of the somatic cell source. Interestingly, we observe that the reprogramming efficiency of somatic cell lines inversely correlates with the amount of methylation change needed to acquire pluripotency. Additionally, we determine that both shared and lines-pecific epigenetic aberrations in hiPSCs can directly translate into changes in gene expression in both the pluripotent and differentiated states. Significantly, our analysis of different hiPSC lines from multiple cell types of origin allow us to identify a reprogramming-specific epigenetic signature comprised of nine aberrantly methylated genes that is able to segregate hESC and hiPSC lines regardless of the somatic cell source or differentiation state.