Journal
CELL REPORTS
Volume 21, Issue 2, Pages 308-315Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.060
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Society for the Promotion of Science [KAKENHI 16H06153]
- Health Labour Science Research Grant
- Takeda Science Foundation grant
- Healthcare New Frontier Policy, Kanagawa Prefecture, Japan
- Division of Genomic Technologies, RIKEN Center for Life Science Technologies
- RIKEN Preventive Medicine and Diagnosis Innovation Program
- RIKEN Junior Research Associate Program
- Grants-in-Aid for Scientific Research [16H06153, 17H03615] Funding Source: KAKEN
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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 poly-morphisms, 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.
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