Reduction of genome reprogramming-associated mutations

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02689
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: Araki Ryoko 国立研究開発法人量子科学技術研究開発機構, 量子生命科学研究所, 上席研究員 (40392211)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ゲノム初期化 / iPS細胞 / 点突然変異 / マイクロサテライト

Outline of Final Research Achievements

We showed that genome reprogramming is accompanied by a transient reduction in DNA repair activity, leading to the occurrence of numerous mutations. On the other hand, we also reported the existence of iPS cells with fewer mutations (erythroblast-derived iPSCs). In this study, we have further elucidated the mechanism of mutagenesis in order to further reduce mutations in iPS cells. By analyzing many sister iPSC lines established from the same somatic cell population, we have clearly demonstrated that almost all the mutations observed in iPS cells are de novo, and have also revealed new iPS cell-specific mutagenesis mechanisms, including a marked increase in the frequency of C>T transitions by deamination, a close relationship between DNA demethylation and C>T transitions, and an increase in the C>T mutations in a specific retrotransposon family.

Free Research Field

ゲノム生物学

Academic Significance and Societal Importance of the Research Achievements

同一のゲノムを持つ細胞を異なる形質の細胞へと分化させるエピゲノム制御は、多細胞生物の根源的機構である。エピゲノム変動はゲノム変異を起こさないと信じられてきたが、iPS細胞や核移植ES細胞などエピゲノム状態の大規模再編により創出される多能性幹細胞ゲノムに多くの変異が検出され両者の密接な関係が示唆された。この分子機構の解明はゲノム初期化機構の理解に大きく貢献するだけではなく医学利用の観点からも極めて重要である。実際、iPS細胞の臨床利用が始まっており、将来の利用拡大も強く期待されていることから、iPS細胞及びその由来細胞の全変異の把握はもとより、ゲノム安定性の分子機構解明が喫緊の課題となっている。