Development of Experimental System and Analysis of Transgenerational Epigenetic Inheritance

• Project/Area Number: 15H02509
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Nakano Toru 大阪大学, 生命機能研究科, 教授 (00172370)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥46,280,000 (Direct Cost: ¥35,600,000、Indirect Cost: ¥10,680,000); Fiscal Year 2017: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2016: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2015: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
• Keywords: エピジェネティクス / 生殖細胞 / 遺伝子発現制御 / 精子形成 / 非コードRNA / DNAメチル化 / 発生・分化 / 遺伝子 / 遺伝子発現 / 発現制御 / 遺伝学

Outline of Final Research Achievements

Epigenetic modification is not inherited in general. However, it has been reported that the modification is inherited from parents to progenies. In this study, we tried to analyze such inheritance by using two strategies. One is transgenic mice in which histone modification is altered, and the other is the system using artificial regulation of g erm cell specific small RNAs, piRNAs (PIWI interacting RNAs). Unfortunately, the former strategy does not work by some unknown reasons. In contrast, the latter strategy has enabled us to analyze the mice in which abnormalities of DNA methylation took place in their male germ cells. Meanwhile, we have carried out the molecular mechanisms of piRNA production, which underlie the DNA methylation of male germ cells.

Academic Significance and Societal Importance of the Research Achievements

エピジェネティック遺伝は、疾患が親から子へと伝達されるメカニズムのひとつとして注目され始めている。そういった現象が存在することは明かであるが、解析に適したシステムがあまりないために、大きな興味が抱かれているにもかかわらず、その研究は遅れ気味である。我々が作出し解析をおこないつつある。雄性生殖細胞のDNAメチル化に異常が生じるマウスは、エピジェネティック遺伝の解析に大きなインパクトを与える可能性があることを明らかにすることができた。今後、親から子へと伝達されるDNAメチル化異常が、マウス個体にどのような影響をおよぼすかを明らかにしていく。

Research Products

• [Journal Article] PNLDC1, mouse pre-piRNA Trimmer, is required for meiotic and post-meiotic male germ cell development. (2018)
  • Author(s): Nishimura T, Nagamori I, Nakatani T, Izumi N, Tomari Y, Kuramochi-Miyagawa S, Nakano T.
  • Journal Title: EMBO Rep. Volume: - Issue: 3
  • DOI: 10.15252/embr.201744957
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between PIWIL4-mediated H3K4me2 demethylation and piRNA-dependent DNA methylation. (2018)
  • Author(s): Nagamori, I., Kobayashi, H., Nishimura, T., Yamagishi, R., Katahira, J., Kuramochi-Miyagawa, S., Kono, T., Nakano, T.
  • Journal Title: Cell Reports Volume: 25 Issue: 2 Pages: 350-356
  • DOI: 10.1016/j.celrep.2018.09.017
  • Peer Reviewed / Open Access
• [Journal Article] MIWI2 as an effector of DNA methylation and gene silencing in embryonic male germ cells (2016)
  • Author(s): 7.Kojima-Kita, K., Kuramochi-Miyagawa, S., Ogonuki, N., Ogura, A., Hasuwa, H., Akazawa, T., Inoue, N., Nakano, T.
  • Journal Title: Cell Reports Volume: 16 Issue: 11 Pages: 2819-28
  • DOI: 10.1016/j.celrep.2016.08.027
  • Peer Reviewed / Open Access
• [Journal Article] Stella preserves maternal chromosome integrity by inhibiting 5hmC-dependent gammaH2AX accumulation. (2015)
  • Author(s): Nakatani et al.
  • Journal Title: EMBO Reports Volume: 16 Issue: 5 Pages: 582-589
  • DOI: 10.15252/embr.201439427
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CRISPR/Cas9-mediated reporter knock-in in mouse haploid embryonic stem cells (2015)
  • Author(s): Kimura, Y., Oda, M., Nakatani, T., Sekita, Y., Monfort, A., Wutz, A., Mochizuki, H., and Nakano, T
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 10710-10710
  • DOI: 10.1038/srep10710
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stella controls chromocenter formation through regulation of Daxx expression in 2-cell embryos. (2015)
  • Author(s): Arakawa, T., Nakatani, T., Oda, M., Kimura, Y., Sekita, Y., Kimura, T., Nakamura, T., and Nakano, T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 466 Issue: 1 Pages: 60-60
  • DOI: 10.1016/j.bbrc.2015.08.106
  • Peer Reviewed / Open Access
• [Journal Article] De novo DNA methylation through the 5'-segment of the H19 ICR maintains its imprint during early embryogenesis (2015)
  • Author(s): Matsuzaki, H., Okamura, E., Takahashi, T., Ushiki, A., Nakamura, T., Nakano, T., Hata, K., Fukamizu, A., and Tanimoto, K.
  • Journal Title: Development Volume: 142 Pages: 3833-3844
  • DOI: 10.1242/dev.126003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals. (2015)
  • Author(s): Parrish NF, Fujino K, Shiromoto Y, Iwasaki YW, Ha H, Xing J, Makino A, Kuramochi-Miyagawa S, Nakano T, Siomi H, Honda T, Tomonaga K.
  • Journal Title: RNA. Volume: 21 Issue: 10 Pages: 1691-703
  • DOI: 10.1261/rna.052092.115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trichostatin A specifically improves the aberrant expression of transcription factor genes in embryos produced by somatic cell nuclear transfer. (2015)
  • Author(s): Inoue K, Oikawa M, Kamimura S, Ogonuki N, Nakamura T, Nakano T, Abe K, Ogura A.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 10127-10127
  • DOI: 10.1038/srep10127
  • Peer Reviewed / Open Access
• [Journal Article] Global DNA hypomethylation coupled to cellular transformation and metastatic ability. (2015)
  • Author(s): Funaki S, Nakamura T, Nakatani T, Umehara H, Nakashima H, Okumura M, Oboki K, Matsumoto K, Saito H, Nakano T.
  • Journal Title: FEBS lett. Volume: 589 Issue: 24PartB Pages: 4053-60
  • DOI: 10.1016/j.febslet.2015.11.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 小児白血病がんとエピジェネティクス (2018)
  • Author(s): 仲野 徹
  • Organizer: 第40回近畿小児血液・がん研究会
  • Invited
• [Presentation] エピジェネティクス入門 (2017)
  • Author(s): 仲野 徹
  • Organizer: 第36回日本臨床運動療法学会
  • Invited
• [Presentation] エピジェネティクスとは何か (2017)
  • Author(s): 仲野 徹
  • Organizer: 第59回日本小児血液・がん学会 特別講演
  • Invited
• [Presentation] エピジェネティクス入門 (2016)
  • Author(s): 仲野 徹
  • Organizer: 第104回日本泌尿器科学会総会
  • Invited
• [Presentation] DNA Methylation and Gene Silencing of Retrotransposons by piRNA in Embryonic Male Germ Cells (2015)
  • Author(s): 仲野 徹
  • Organizer: Conferences Jacques Monod DNA Methylation and Demethylation
  • Place of Presentation: フランス
  • Year and Date: 2015-11-15
  • Int'l Joint Research / Invited
• [Presentation] エピジェネティクス研究 私史 (2015)
  • Author(s): 仲野 徹
  • Organizer: 日本エピジェネティクス研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-25
• [Presentation] エピジェネティクス入門 (2015)
  • Author(s): 仲野 徹
  • Organizer: 第104回日本病理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-05-01
  • Invited