Genetic Variation, Not Cell Type of Origin, Underlies the Majority of Identifiable Regulatory Differences in iPSCs.
Genetic Variation, Not Cell Type of Origin, Underlies the Majority of Identifiable Regulatory Differences in iPSCs.
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DOI：
10.1371/journal.pgen.1005793
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发表时间：
2016-01
期刊：
影响因子：
4.5
通讯作者：
Gilad Y
中科院分区：
文献类型：
--
作者：
Burrows CK;Banovich NE;Pavlovic BJ;Patterson K;Gallego Romero I;Pritchard JK;Gilad Y
诱导多能干细胞(IPSCs)的出现使我们能够从容易获得的体细胞组织中产生多能细胞，从而彻底改变了人类的遗传学。这项技术可以对再生医学产生巨大的影响，但IPSCs也代表着复杂人类表型研究的范式转变，包括基因调控和疾病。然而，IPSC模型系统的一个悬而未决的警告是，重新编程的IPSC在多大程度上保留了其前体体细胞的残留表型。为了直接解决这个问题，我们使用了一个有效的研究设计来比较来自两种常用体细胞前体细胞的IPSCs之间的调节表型。我们发现来自不同体细胞前体的IPSCs之间在DNA甲基化和基因表达水平上的差异非常小。相反，我们证明了遗传变异与DNA甲基化和基因表达水平上的大多数可识别变异有关。我们发现，来源的细胞类型只对IPSCs的基因表达水平和DNA甲基化影响很小，遗传变异是不同捐赠者IPSCs之间调控差异的主要驱动因素。我们的发现表明，使用IPSCs的研究应该关注其他个体，而不是同一个体的克隆人。诱导多能干细胞(IPSCs)是一种新的强大的细胞类型，为科学家提供了在体外模拟复杂的人类疾病的能力。这些细胞可以被冷冻保存，然后进行扩增，为同一个体提供可再生的细胞来源。IPSCs可以由人体内的各种体细胞制成，许多实验室已经从血液和皮肤细胞中制造出了IPSCs。我们询问来源的细胞类型是否影响重新编程的IPSCs的甲基化和基因表达模式。我们的发现表明，在IPSCs中，起源于细胞类型的调控残留物非常少。换句话说，ipscs之间的大部分差异可以归因于个体遗传。我们的发现表明，使用IPSCs的研究应该专注于获得更多的个体，而不是从同一个个体获得额外的克隆。我们警告说，我们目前的发现仅限于IPSCs，还需要进一步的研究来解决分化细胞类型中的体细胞记忆问题。
The advent of induced pluripotent stem cells (iPSCs) revolutionized human genetics by allowing us to generate pluripotent cells from easily accessible somatic tissues. This technology can have immense implications for regenerative medicine, but iPSCs also represent a paradigm shift in the study of complex human phenotypes, including gene regulation and disease. Yet, an unresolved caveat of the iPSC model system is the extent to which reprogrammed iPSCs retain residual phenotypes from their precursor somatic cells. To directly address this issue, we used an effective study design to compare regulatory phenotypes between iPSCs derived from two types of commonly used somatic precursor cells. We find a remarkably small number of differences in DNA methylation and gene expression levels between iPSCs derived from different somatic precursors. Instead, we demonstrate genetic variation is associated with the majority of identifiable variation in DNA methylation and gene expression levels. We show that the cell type of origin only minimally affects gene expression levels and DNA methylation in iPSCs, and that genetic variation is the main driver of regulatory differences between iPSCs of different donors. Our findings suggest that studies using iPSCs should focus on additional individuals rather than clones from the same individual. Induced pluripotent stem cells (iPSCs) are a new and powerful cell type that provides scientists the ability to model complex human diseases in vitro. These cells can be cryopreserved and later expanded, providing a renewable source of cells from the same individual. iPSCs can be made from a variety of somatic cells in the body and many labs have created them from blood and skin cells. We asked whether the cell type of origin impacts methylation and gene expression patterns in the reprogrammed iPSCs. Our findings indicate that there are remarkably few regulatory remnants of the cell type of origin in the iPSCs. In other words, most of the variation between iPSCs can be attributed to individual genetics. Our findings suggest that studies using iPSCs should focus on obtaining additional individuals rather than additional clones from the same individual. We caution that our current findings are limited to iPSCs and further studies are needed to address the question of somatic memory in differentiated cell types.