Functional elucidation of maintenance DNA methyltransferase DNMT1 in neurons

• Project/Area Number: 19K06502
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: National Institute of Advanced Industrial Science and Technology
• Principal Investigator: Namihira Masakazu 国立研究開発法人産業技術総合研究所, 生命工学領域, 研究グループ長 (60379534)
• Co-Investigator(Kenkyū-buntansha): 新木 和孝 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 (60514255) ; 齋藤 裕 国立研究開発法人産業技術総合研究所, 情報・人間工学領域, 主任研究員 (60721496)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: DNAメチル化 / DNMT1 / 神経細胞 / エピジェネティクス

Outline of Research at the Start

本研究の目的は、マウスとヒトの神経細胞（ニューロン）において、分裂を終えた細胞での機能が未知である維持型DNAメチル化酵素DNMT1に着目し、その機能解明と、精神・発達障害との関連を明示することである。特に本研究は、ニューロン特異的にDNMT1を過剰発現する申請者が独自に開発した新規遺伝子改変マウスを利用し、生化学的解析、及び、行動学的解析を実施することで、疾患との関連を示す。

Outline of Final Research Achievements

The aim of this study was to elucidate the role of the DNA methyltransferase DNMT1 in postmitotic neurons and the association between its dysfunction and psychiatric disorders. The results revealed that DNMT1 is involved in the maintenance of DNA methylation in enhancer regions of genes that are essential for the neuronal functions. Furthermore, we found that DNMT1 also contributes to DNA demethylation in specific genomic regions. We also suggested that DNMT1 plays a similar role in human neurons as in mouse neurons. These results provide novel insights into the function of DNMT1 and suggest that dysfunction of DNMT1 contributes to the pathogenesis of neurological diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の遂行から、ニューロンにおけるDNMT1が担うゲノム領域特異的なDNAメチル化制御機構について新たな知見を提示することができた。加えて、DNMT1が脳神経の発達と機能発現に重要な役割を担うとともに、その機能異常が精神疾患の発症に関わることを示唆することができている。このことは、DNMT1やDNAメチル化が、精神疾患のみならず発達障害や幼児期の環境ストレスによるPTSDなどの治療の標的なる得る可能性を示唆している。従って、本研究の結果は、学術的価値が高いだけでなく、臨床的側面からも重要な意義を持つと考えている。

Research Products

• [Journal Article] Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells (2022)
  • Author(s): Murotomi Kazutoshi、Kagiwada Harumi、Hirano Kazumi、Yamamoto Shoko、Numata Noriaki、Matsumoto Yo、Kaneko Hidekazu、Namihira Masakazu
  • Journal Title: Journal of Cellular Physiology Volume: 238 Issue: 2 Pages: 434-446
  • DOI: 10.1002/jcp.30940
  • Peer Reviewed
• [Journal Article] Biosynthesis of S-adenosyl-methionine enhances aging-related defects in Drosophila oogenesis (2022)
  • Author(s): Hayashi Yoshiki、Kashio Soshiro、Murotomi Kazutoshi、Hino Shinjiro、Kang Woojin、Miyado Kenji、Nakao Mitsuyoshi、Miura Masayuki、Kobayashi Satoru、Namihira Masakazu
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41598-022-09424-1
  • Peer Reviewed / Open Access
• [Journal Article] Protein lactylation induced by neural excitation (2021)
  • Author(s): Hagihara Hideo、Shoji Hirotaka、Otabi Hikari、Toyoda Atsushi、Katoh Kaoru、Namihira Masakazu、Miyakawa Tsuyoshi
  • Journal Title: Cell Reports Volume: 37 Issue: 2 Pages: 109820-109820
  • DOI: 10.1016/j.celrep.2021.109820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Machine learning approach for discrimination of genotypes based on bright-field cellular images (2021)
  • Author(s): Suzuki Godai、Saito Yutaka、Seki Motoaki、Evans-Yamamoto Daniel、Negishi Mikiko、Kakoi Kentaro、Kawai Hiroki、Landry Christian R.、Yachie Nozomu、Mitsuyama Toutai
  • Journal Title: npj Systems Biology and Applications Volume: 7 Issue: 1 Pages: 1-8
  • DOI: 10.1038/s41540-021-00190-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein lactylation induced by neural excitation (2021)
  • Author(s): Hideo Hagihara, Hirotaka Shoji, Hikari Otabi, Atsushi Toyoda, Kaoru Katoh, Masakazu Namihira, Tsuyoshi Miyakawa
  • Journal Title: bioRxiv Volume: 10.1101/2021.02.02.428370 Pages: 428362-428362
  • DOI: 10.1101/2021.02.02.428370
  • Open Access
• [Journal Article] Evotuning protocols for Transformer-based variant effect prediction on multi-domain proteins (2021)
  • Author(s): Yamaguchi Hideki、Saito Yutaka
  • Journal Title: bioRxiv Volume: - Pages: 434175-434175
  • DOI: 10.1101/2021.03.05.434175
  • Open Access
• [Journal Article] Existence and possible roles of independent non-CpG methylation in the mammalian brain (2020)
  • Author(s): Lee Jong-Hun、Saito Yutaka、Park Sung-Joon、Nakai Kenta
  • Journal Title: DNA Research Volume: 27 Issue: 4
  • DOI: 10.1093/dnares/dsaa020
  • Peer Reviewed / Open Access
• [Journal Article] Predicting antibody affinity changes upon mutations by combining multiple predictors (2020)
  • Author(s): Kurumida Yoichi、Saito Yutaka、Kameda Tomoshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 19533-19533
  • DOI: 10.1038/s41598-020-76369-8
  • Peer Reviewed / Open Access
• [Presentation] 脳の機能と老化を制御する代謝とエピジェネティクスのクロストーク (2023)
  • Author(s): 波平昌一
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] 神経細胞におけるDNMT1によるエンハンサー領域のメチル化制御 (2019)
  • Author(s): 波平昌一、木村文香、齋藤裕、松田泰斗、今村拓也、大塚まき、五十嵐勝秀、三浦史仁、伊藤隆司、堅田明子、中島欽一
  • Organizer: 第13回エピジェネティクス研究会年会
• [Presentation] DNA-methyltransferase 1 participates in methylation of neuronal enhancer in post-mitotic neuron of mammalian brain. (2019)
  • Author(s): Masakazu Namihira, Ayaka Kimura, Yutaka Saito, Taito Matsuda, Takuya Imamura, Hirofumi Noguchi, Maky Otsuka I., Katsuhide Igarashi, Kinichi Nakashima
  • Organizer: Neuroscience 2019, Society for Neuroscience, Chicag, IL
  • Int'l Joint Research