Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells
Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells
复制标题
诱导多能干细胞中从头点突变的热点
DOI：
10.1016/j.celrep.2017.09.060
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发表时间：
2017
期刊：
影响因子：
8.8
通讯作者：
Murakawa Yasuhiro
中科院分区：
文献类型：
--
作者：
Yoshihara Masahito;Araki Ryoko;Kasama Yasuji;Sunayama Misato;Abe Masumi;Nishida Kohji;Kawaji Hideya;Hayashizaki Yoshihide;Murakawa Yasuhiro
诱导多能干细胞（iPSC）是通过体细胞的直接重编程产生的，并且在新疗法中具有很大的前景。然而，一些研究报告了iPSC基因组中的遗传变异。在这里，我们研究了在表观遗传状态的背景下，通过小鼠和人iPSC的全基因组测序鉴定的点突变。与引起疾病的单核苷酸多态性相反，在重编程过程中引入的从头点突变在蛋白质编码基因和开放染色质区域（包括转录因子结合位点）中的代表性不足。相反，这些突变优先发生在结构浓缩的核纤层相关异染色质结构域，表明染色质组织是一个因素，可以在iPSC基因组中的区域突变率的偏见。突变特征分析表明，与重编程相关的氧化应激可能是点突变的原因。总而言之，我们的研究提供了对iPSC基因组突变景观的更深入了解，为基于iPSC的细胞疗法的翻译铺平了重要道路。
Induced pluripotent stem cells (iPSCs) are generated by direct reprogramming of somatic cells and hold great promise for novel therapies. However, several studies have reported genetic variations in iPSC genomes. Here, we investigated point mutations identified by whole-genome sequencing in mouse and human iPSCs in the context of epigenetic status. In contrast to disease-causing single-nucleotide polymorphisms, de novo point mutations introduced during reprogramming were underrepresented in protein-coding genes and in open chromatin regions, including transcription factor binding sites. Instead, these mutations occurred preferentially in structurally condensed lamina-associated heterochromatic domains, suggesting that chromatin organization is a factor that can bias the regional mutation rate in iPSC genomes. Mutation signature analysis implicated oxidative stress associated with reprogramming as a likely cause of point mutations. Altogether, our study provides deeper understanding of the mutational landscape of iPSC genomes, paving an important way toward the translation of iPSC-based cell therapy.