Towards understanding the role for DNMT1 to establish Polycomb-mediated gene silencing

2020 Fiscal Year Final Research Report

• Project/Area Number: 16H02622
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Koseki Haruhiko 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (40225446)
• Project Period (FY): 2016-04-01 – 2021-03-31
• Keywords: DNMT1 / ポリコム群遺伝子 / CpGアイランド / NP95/UHRF1 / RNF20

Outline of Final Research Achievements

In mammals, CpG dinucleotides are recognized by not only DNA methylation mechanisms but also Polycomb group (PcG)-related silencing mechanisms. We hypothesized these two distinct mechanism may functionally interact at CpG dinucleotides and addressed the impacts of DNA methylation maintenance mechanisms mediated by DNMT1 and NP95 on PcG-mediated silencing. Intriguingly, we found target binding and silencing by PcG factors required DNMT1 but not NP95. Instead, NP95 was required for de-repression of PcG targets induced by DNMT1 depletion. Biochemical studies revealed NP95 is involved to mediate ubiquitination of EED, a core component of PcG complexes, and its proteasomal degradation. This study revealed an unexpected link between DNA methylation mechanisms and PcG factors to mediate PcG-mediated silencing, which contributes to maintain spatiotemporally restricted expression of development/differentiation-related genes to facilitate normal development and maintenance of homeostasis.

Free Research Field

発生学、遺伝学、免疫学

Academic Significance and Societal Importance of the Research Achievements

CpG配列を介したエピジェネティック制御は、発生過程だけではなくがんなどの発症にも強く寄与すること、さらには、その創薬標的になりうることは長く考えられてきた。しかしながら、CpG配列にどのような因子群が作用するのかについて多くのことは知られていなかったため、現実的な創薬戦略の確立には至っていなかった。DNAメチル化制御とポリコム群の間の機能的な連関が明らかになることにより、これらのメカニズムが新たな介入点になりうることが実証された。また、臨床で使用が始められつつあるメチル化阻害剤やポリコム阻害剤の適応拡大や副作用のメカニズム理解に貢献しうる。