De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency
Summary: CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-05-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671119301304 |
| _version_ | 1828370609304764416 |
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| author | Masaki Yagi Mio Kabata Tomoyo Ukai Sho Ohta Akito Tanaka Yui Shimada Michihiko Sugimoto Kimi Araki Keisuke Okita Knut Woltjen Konrad Hochedlinger Takuya Yamamoto Yasuhiro Yamada |
| author_facet | Masaki Yagi Mio Kabata Tomoyo Ukai Sho Ohta Akito Tanaka Yui Shimada Michihiko Sugimoto Kimi Araki Keisuke Okita Knut Woltjen Konrad Hochedlinger Takuya Yamamoto Yasuhiro Yamada |
| author_sort | Masaki Yagi |
| collection | DOAJ |
| description | Summary: CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, was often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs. : In this article, Yamada, Yamamoto and colleagues show that Dnmt3a-mediated DNA methylation occurs at imprinting loci during reprogramming into naive and primed PSCs. Similar de novo ICR methylation is detected in pediatric cancers, which raises the possibility that reprogramming is involved in development of childhood cancers. Keywords: pluripotent stem cells, naive and primed pluripotency, reprogramming, pediatric cancers, DNA methylation, genomic imprinting, CpG islands, Dnmt3a |
| first_indexed | 2024-04-14T06:40:48Z |
| format | Article |
| id | doaj.art-16df7a08bde34afb9cf8bc2e9b4162c2 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-04-14T06:40:48Z |
| publishDate | 2019-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-16df7a08bde34afb9cf8bc2e9b4162c22022-12-22T02:07:20ZengElsevierStem Cell Reports2213-67112019-05-0112511131128De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed PluripotencyMasaki Yagi0Mio Kabata1Tomoyo Ukai2Sho Ohta3Akito Tanaka4Yui Shimada5Michihiko Sugimoto6Kimi Araki7Keisuke Okita8Knut Woltjen9Konrad Hochedlinger10Takuya Yamamoto11Yasuhiro Yamada12Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanDivision of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanDivision of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanDivision of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanInstitute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, JapanInstitute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, JapanDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USADepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan; Corresponding authorDivision of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo 100-0004, Japan; Corresponding authorSummary: CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, was often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs. : In this article, Yamada, Yamamoto and colleagues show that Dnmt3a-mediated DNA methylation occurs at imprinting loci during reprogramming into naive and primed PSCs. Similar de novo ICR methylation is detected in pediatric cancers, which raises the possibility that reprogramming is involved in development of childhood cancers. Keywords: pluripotent stem cells, naive and primed pluripotency, reprogramming, pediatric cancers, DNA methylation, genomic imprinting, CpG islands, Dnmt3ahttp://www.sciencedirect.com/science/article/pii/S2213671119301304 |
| spellingShingle | Masaki Yagi Mio Kabata Tomoyo Ukai Sho Ohta Akito Tanaka Yui Shimada Michihiko Sugimoto Kimi Araki Keisuke Okita Knut Woltjen Konrad Hochedlinger Takuya Yamamoto Yasuhiro Yamada De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency Stem Cell Reports |
| title | De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency |
| title_full | De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency |
| title_fullStr | De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency |
| title_full_unstemmed | De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency |
| title_short | De Novo DNA Methylation at Imprinted Loci during Reprogramming into Naive and Primed Pluripotency |
| title_sort | de novo dna methylation at imprinted loci during reprogramming into naive and primed pluripotency |
| url | http://www.sciencedirect.com/science/article/pii/S2213671119301304 |
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