Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells
Summary: 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717313505 |
| _version_ | 1811278030387019776 |
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| author | Masahito Yoshihara Ryoko Araki Yasuji Kasama Misato Sunayama Masumi Abe Kohji Nishida Hideya Kawaji Yoshihide Hayashizaki Yasuhiro Murakawa |
| author_facet | Masahito Yoshihara Ryoko Araki Yasuji Kasama Misato Sunayama Masumi Abe Kohji Nishida Hideya Kawaji Yoshihide Hayashizaki Yasuhiro Murakawa |
| author_sort | Masahito Yoshihara |
| collection | DOAJ |
| description | Summary: 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. : Yoshihara et al. show that de novo point mutations introduced during iPSC reprogramming preferentially occur in structurally condensed lamina-associated heterochromatic domains and exhibit an oxidative stress-induced DNA damage mutation signature. This study provides better characterization of iPSC mutations at the whole-genome level and accelerates the translation of iPSC-based cell therapies. Keywords: iPSCs, genomics, point mutation, epigenetics, heterochromatin, lamina-associated domains, iPSC-based cell therapy |
| first_indexed | 2024-04-13T00:28:30Z |
| format | Article |
| id | doaj.art-fdc5f976fc674c8289aa6a7624f8ebd0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T00:28:30Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fdc5f976fc674c8289aa6a7624f8ebd02022-12-22T03:10:33ZengElsevierCell Reports2211-12472017-10-01212308315Hotspots of De Novo Point Mutations in Induced Pluripotent Stem CellsMasahito Yoshihara0Ryoko Araki1Yasuji Kasama2Misato Sunayama3Masumi Abe4Kohji Nishida5Hideya Kawaji6Yoshihide Hayashizaki7Yasuhiro Murakawa8Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDepartment of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanDepartment of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanDepartment of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanDepartment of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanDepartment of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanDivision of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan; Preventive Medicine and Applied Genomics Unit, RIKEN Advanced Center for Computing and Communication, Yokohama, Kanagawa 230-0045, JapanRIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, JapanDivision of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan; Corresponding authorSummary: 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. : Yoshihara et al. show that de novo point mutations introduced during iPSC reprogramming preferentially occur in structurally condensed lamina-associated heterochromatic domains and exhibit an oxidative stress-induced DNA damage mutation signature. This study provides better characterization of iPSC mutations at the whole-genome level and accelerates the translation of iPSC-based cell therapies. Keywords: iPSCs, genomics, point mutation, epigenetics, heterochromatin, lamina-associated domains, iPSC-based cell therapyhttp://www.sciencedirect.com/science/article/pii/S2211124717313505 |
| spellingShingle | Masahito Yoshihara Ryoko Araki Yasuji Kasama Misato Sunayama Masumi Abe Kohji Nishida Hideya Kawaji Yoshihide Hayashizaki Yasuhiro Murakawa Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells Cell Reports |
| title | Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells |
| title_full | Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells |
| title_fullStr | Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells |
| title_full_unstemmed | Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells |
| title_short | Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells |
| title_sort | hotspots of de novo point mutations in induced pluripotent stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717313505 |
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