Kevin Eggan2014-02-27 12:34 PM

人体细胞突变编码诱导多能干细胞。 Somatic coding mutations in human induced pluripotent stem cells.

论文摘要

定义的转录因子能诱导成年哺乳动物细胞的表观遗传重编程变成诱导性多能干细胞。尽管DNA因子在某些重编程方法中是完整的,但我们仍然不清楚基因组是否能在单核苷酸水平保持不变。我们在此表明22条人体诱导多能干细胞(hiPS)细胞谱系通过五种不同方法被重编程,每种方法平均包含了采样区域中5个蛋白质编码点突变(估计每个外显子具有6个蛋白质编码点突变)。大部分突变是异义,无意义或拼接的变量并富集在突变的或能起致癌作用的基因中。这些与重编程相关的突变至少有一半低频预先存在于成纤维前体细胞中而剩下部分的则发生在期间或重编程后。因此hiPS细胞除表观遗传修饰外还获得了基因遗传修饰。广泛的遗传筛查应该成为一个标准程序从而使得我们能在临床推广前确保hiPS细胞安全性。


Abstract

Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use.

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Kevin Eggan

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