Development of pericentromere-specific epigenome editing technology and application to new human cerebral development model

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15056
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: National Institute of Advanced Industrial Science and Technology
• Principal Investigator: Hirano Kazumi 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (40707709)
• Project Period (FY): 2021-03-01 – 2022-03-31
• Keywords: 神経疾患 / 神経発生 / 脳オルガノイド / 神経幹細胞 / エピゲノム

Outline of Final Research Achievements

In recent years, "cerebral organoid", a method for creating a three-dimensional in vitro model of human cerebral development, has been reported. However, it has been pointed out that the genomic DNA is abnormally hypomethylated in the region near the centromere (pericentromere) compared to the fetal cerebrum. Therefore, it is possible that the current cerebral organoid production method cannot mimic normal cerebral development. The purpose of this research project is to create a cerebral organoid that eliminates DNA methylation abnormalities. First, we started to create a novel cerebral organoid using neural stem cells derived from human fetal cerebral cortex, and obtained certain results. Using this technology as a basic technology, we have established a technology for searching factors that contribute to DNA methylation and evaluating hmC exact amount.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

近年、ヒト大脳発生の３次元in vitroモデル「大脳オルガノイド」の作成法が報告されたが、胎児大脳と比較し、セントロメア近傍領域（ペリセントロメア）におけるゲノムDNAの異常な低メチル化が指摘されている。この状態は精神遅滞を伴うICF症候群と共通する表現型であり、現状の大脳オルガノイド作成法では正常な大脳発生を再現できていない可能性がある。そこで、本研究課題では、DNAメチル化異常を解消した大脳オルガノイドの作成を目的としている。本課題により、正常な大脳発生モデルが確立され、エピゲノム異常による神経疾患の治療・創薬への貢献が可能となる。