2018 Fiscal Year Final Research Report
Epigenetics from zygotic genome activation to implantation controlling the totipotency of the preimplantationembryo
| Project/Area Number |
16H05042
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Integrative animal science
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
塚本 智史 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 技術安全部, 主幹研究員(定常) (80510693)
宮本 圭 近畿大学, 生物理工学部, 講師 (40740684)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | マウス初期胚 / 胚性ゲノムの活性化 / エピジェネティクス / 発生と分化 |
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| Outline of Final Research Achievements |
During mouse preimplantation development, a new developmental program starts through chromatin remodeling. Histone H4 Lysine 20 (H4K20) monomethylation has been reported to control gene expression and DNA damage. However, little is known about the role of methylation by SETD8 in mouse preimplantation development. In the present study, we revealed that SETD8 regulated cell cycle progression during mouse preimplantation development. Although it is known that SETD8 methylates not only H4K20 but also non-histone proteins such as p53 to control its function, we found that developmental arrest of SETD8-inhibited embryos was due to inhibition of H4K20 monomethylation. In addition, development delay caused by transient inhibition of SETD8 was rescued by inhibition of ATR pathway, which play crucial role in DNA damage repairment and cell cycle checkpoint. These results suggest that SETD8-mediated H4K20 monomethylation regulate cell cycle progression in mouse preimplantation development.
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| Free Research Field |
生殖生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、ヒストンH4K20ののメチル化に関与するSETD8の機能を阻害すると、胚の発生停止や発生遅延を引き起こすことを明らかにした。SETD8阻害時に、DNA修復に関わるATR経路を同時に抑制すると、細胞周期が正常に進むことも明らかになり、体外で培養された受精卵が常にDNA修復を必要としていることが示唆された。このことはこれまでに指摘されてこなかったことであり、学術的に大きな意義を持つ。また、ヒトの生殖補助医療においても、できるだけDNA損傷が起こらないような培養環境を作っていくことで、より自然な発生を誘導し、正常な受胎を支持する技術開発にも繋がり、社会的にも大きな意義を持つ。
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