Elucidation of zebrafish Dnmt3aa target genomic regions and region-specific factors in hematopoiesis

• Project/Area Number: 18K06185
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: Hiroshima University
• Principal Investigator: Kikuchi Yutaka 広島大学, 統合生命科学研究科(理), 教授 (20286438)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); 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); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 転写終結 / Dnmt3a / ゼブラフィッシュ / dnmt3a / DNAメチル化 / Dnmt3aa

Outline of Final Research Achievements

The de novo DNA methyltransferase Dnmt3a regulates gene expression through methylation modification of genomic DNA. DNA methylation of promoters in vertebrates has been reported to function in the regulation of gene expression. However, the role of DNA methylation in the transcription termination region has not yet been reported. In this study, we generated a maternal embryonic knockout mutant (MZdnmt3aa-/-) of the zebrafish dnmt3aa gene, which is a homologue of the mammalian Dnmt3a gene, to elucidate the function of Dnmt3aa in the transcription termination process. We found that DNA hypomethylation in the transcription termination region is involved in the regulation of transcription termination by comprehensive gene expression analysis and whole genome bisulfite sequencing analysis using MZdnmt3aa-/- embryos.

Academic Significance and Societal Importance of the Research Achievements

脊椎動物におけるプロモーターのDNAメチル化は、遺伝子発現制御に機能する事が報告されているが、転写終結領域におけるDNAメチル化の役割に関しては、未だ報告はなされていない。本研究課題では、世界で初めて転写終結領域におけるDNA低メチル化が、転写終結制御に関与している事を見出した。DNAのメチル化制御は、癌の悪性化にも関している事が知られているため、本研究成果は癌治療にも役立つと考えられる。

Research Products

• [Journal Article] Anticancer polymers designed for killing dormant prostate cancer cells. (2019)
  • Author(s): Takahashi, H., Yumoto, K., Yasuhara, K., Enrico T. Nadres, T.E., Kikuchi, Y., Taichman, R.S., and Kuroda, K.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1096-1106
  • DOI: 10.1038/s41598-019-53859-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anticancer polymers designed for killing dormant prostate cancer cells. (2019)
  • Author(s): Takahashi, T., Yumoto, K., Yasuhara, K., Enrico T. Nadres, T.E., Kikuchi, Y., Taichman, R.S., and Kuroda, K.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1096-1096
  • DOI: 10.1038/s41598-018-36608-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The N-terminal domain of Gastrulation brain homeobox 2 (Gbx2) is required for iridophore specification in zebrafish. (2018)
  • Author(s): Hozumi, S., Shirai, M., Wang, J., Aoki, S., and Kikuchi, Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 502 Issue: 1 Pages: 104-109
  • DOI: 10.1016/j.bbrc.2018.05.128
  • Peer Reviewed
• [Journal Article] Leucine/glutamine and v-ATPase/lysosomal acidification via mTORC1activation are required for position-dependent regeneration. (2018)
  • Author(s): Takayama, K., Muto, A., and Kikuchi, Y.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8278-8278
  • DOI: 10.1038/s41598-018-26664-2
  • NAID: 120006800842
  • Peer Reviewed / Open Access
• [Journal Article] Unusual light-reflecting pigment cells appear in the Xenopus neural tube culture system in the presence of guanosine. (2018)
  • Author(s): Fukuzawa, T. and Kikuchi, Y.
  • Journal Title: Tissue and Cell Volume: 54 Pages: 55-58
  • DOI: 10.1016/j.tice.2018.08.003
  • Peer Reviewed
• [Presentation] 哺乳類における運動器の筋―腱接合部の形成と成熟機構の統合的理解 (2020)
  • Author(s): 高橋 治子、山本 泰久、雲山 一慧、池田 皓、Mingcong Xu、菊池 裕
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] 転写終結は、Dnmt3aによる転写終結部位のDNAメチル化レベルと関連がある (2020)
  • Author(s): 白井 均樹、奈良 拓也、高橋 治子、Chen Yuan、高山 和也、廣瀬 湧大、粟津 暁紀、藤井 雅史、下田 修義、菊池 裕
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] 3次元in vitro培養系によるがん微小環境理解のための組織構成的アプローチ (2019)
  • Author(s): 高橋 治子、菊池 裕
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] ゼブラフィッシュDnmt3aaが標的とするゲノム領域の同定 (2019)
  • Author(s): 白井 均樹、高橋 治子、高山 和也、下田 修義、菊池 裕
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Comprehensive analysis of miRNAs in cancer stem-like cells (2019)
  • Author(s): Jie Huang, Haruko Takahashi, Mayuko Nishi, Akihide Ryo, Yutaka Kikuchi
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Tumor invasion and progression are associated with cholinergic-nerves via nicotinic acetylcholine receptors (2019)
  • Author(s): Mohamed N. Bakr, Shunya Hozumi, Hiroya Katayama, Haruko Takahashi, Yukinari Haraoka, Tohru Ishitani, Yutaka Kikuchi
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Analysis of target genomic regions of DNA methyltransferase3aa (Dnmt3aa) in zebrafish. (2018)
  • Author(s): Masaki Shirai, Kazuya Takayama, Ikumi Taya, Nobuyoshi Shimoda, and Yutaka Kikuchi
  • Organizer: 第70回日本細胞生物学会
• [Presentation] Study on the relationship between neural gene expression and dedifferentiation in early stage of carcinogenesis. (2018)
  • Author(s): Shunya Hozumi, Hiroya Katayama, Jia Zeyuan, and Yutaka Kikuchi
  • Organizer: 第70回日本細胞生物学会
• [Presentation] Control of cell proliferation in zebrafish fin regeneration. -Position-dependent cell proliferation-. (2018)
  • Author(s): Yutaka Kikuchi
  • Organizer: 沖縄科学技術大学院大学（OIST）セミナー
  • Invited
• [Presentation] In vitro analysis of tumor microenvironment formation process around cancer cells. (2018)
  • Author(s): Haruko Takahashi and Yutaka Kikuchi
  • Organizer: 第41回日本分子生物学年会
• [Presentation] Study on function of neuroendocrine-like cell in cancer progression in a zebrafish melanoma model. (2018)
  • Author(s): Shunya Hozumi, Hiroya Katayama, Yukinari Haraoka, Tohru Ishitani, and Yutaka Kikuchi
  • Organizer: 第41回日本分子生物学年会
• [Presentation] Identification of target genomic regions of DNA methyltransferase3aa (Dnmt3aa) in zebrafish. (2018)
  • Author(s): Masaki Shirai, Kazuya Takayama, Ikumi Taya, Nobuyoshi Shimoda, and Yutaka Kikuchi
  • Organizer: 第41回日本分子生物学年会
• [Remarks]
  • URL: https://www.bio.hiroshima-u.ac.jp/devbio/