Genetic background drives transcriptional variation in human induced pluripotent stem cells.
Genetic background drives transcriptional variation in human induced pluripotent stem cells.
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DOI：
10.1371/journal.pgen.1004432
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Gaffney D
中科院分区：
文献类型：
--
作者：
Rouhani F;Kumasaka N;de Brito MC;Bradley A;Vallier L;Gaffney D
利用来自不同捐赠者的不同组织，使用不同的重编程载体来产生人类iPS细胞。然而，这些细胞系是异质性的，这限制了它们在疾病建模和个性化医学中的应用。为了探索这种异质性的基础，我们在标准化条件下从同一组来自多个捐赠者的体细胞组织中产生了25个iPS细胞系。比较了来自每个细胞系的RNA-SEQ数据集，以确定导致转录异质性的主要因素。我们发现个体供体之间的遗传差异是品系间转录差异的主要原因。相比之下，起源于体细胞的残留特征，即所谓的表观遗传记忆，对转录变异的贡献相对较小。因此，潜在的遗传背景变异是导致人iPS细胞系之间大部分异质性的原因。我们的结论是，表观遗传效应在HiPSCs中是最小的，并且HiPSCs是一个稳定、健壮和强大的平台，用于大规模研究个体之间的遗传差异的功能。我们的数据还表明，未来使用HiPSCs作为模型系统的研究应该把大部分精力集中在收集大量捐赠者上，而不是从同一捐赠者那里产生大量的线路。人类诱导多能干细胞(HIPS)是研究人类疾病和发育的一个潜在的强大的模型系统，也是个性化药物的资源。然而，据报道，HIPS细胞表现出很大的异质性，这可能限制其作为模型系统的使用。显然，对异质性来源的了解是更深入地了解人类iPS细胞用于基础和治疗应用的关键。这种异质性的一个来源被认为是对HIPS细胞来源的成年体细胞的“记忆”，但支持这一观点的证据很少。我们已经从来自不同捐赠者的一组体细胞类型中产生了一组人类iPS细胞。我们的研究表明，来自不同体细胞来源但来自同一供体(即具有相同基因组)的细胞系比来自相同组织类型但来自不同供体的细胞系更相似。一旦考虑到遗传变化，来自不同组织的iPS细胞之间的基因表达的方方面面，包括mRNA水平、剪接和印记都高度相似。因此，先前描述的细胞系之间的大部分转录变异很可能是遗传起源的。
Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor. Human induced pluripotent stem (hiPS) cells are a potentially powerful model system for studying human disease and development, and a resource for personalized medicine. However, it has been reported that hiPS cells exhibit substantial heterogeneity which could limit their use as model systems. Clearly, knowledge of the source of heterogeneity is key for deeper understanding of the use of human iPS cells for basic and therapeutic applications. One source of this heterogeneity has been presumed to be “memory” of the adult somatic cell from which the hIPS cells were derived, but the evidence to support this view is scant. We have generated a set of human iPS cells from a set of somatic cell types from different donors. Our study shows that cell lines from different somatic sources but from the same donor (i.e. with the same genome) are more similar than cell lines isolated from the same tissue type but from different donors. Once genetic changes are accounted for, all aspects of gene expression, including mRNA levels, splicing and imprinting are highly similar between iPS cells derived from different human tissues. Thus, most of the previously described transcriptional variation between cell lines is likely to be genetic in origin.
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