A new therapeutic strategy for autoimmune diseases through epigenome editing

• Project/Area Number: 17H03613
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: Gunma University
• Principal Investigator: Hatada Izuho 群馬大学, 生体調節研究所, 教授 (50212147)
• Co-Investigator(Kenkyū-buntansha): 堀居 拓郎 群馬大学, 生体調節研究所, 准教授 (00361387) ; 森田 純代 群馬大学, 生体調節研究所, 助教 (40589264) ; 澁谷 海大 群馬大学, 生体調節研究所, 研究員 (70786839)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: エピゲノム / ゲノム編集 / エピゲノム編集 / エピジェネティクス / ゲノム

Outline of Final Research Achievements

A powerful epigenome editing technique is required for the generation of stable regulatory T cells. For that purpose, we improved the SunTag method to recruit VP64 in addition to TET, which has been developed so far, and were able to perform more powerful epigenome editing. In other words, dCas9-SunTag and scFv-TET plus an anti-GCN4 peptide antibody (scFv-X) fused to another epigenomic factor allowed both TET1 and Factor X to be recruited to their targets with a single sgRNA, thus synergistically activating the target genes. In particular, the most synergistic effect was achieved when VP64 was used as X.

Academic Significance and Societal Importance of the Research Achievements

本研究は自己免疫疾患の多くに適用できる可能性があるとともに、特定の遺伝子を特異的にねらったエピゲノム療法という新たな治療戦略を提供する。この戦略は遺伝子の発現量を回復させることにより治療できる様々な疾患に応用可能である。また遺伝子治療と異なり一過性の遺伝子発現あるいはリコンビナントタンパク質の導入でも治療は可能であるので遺伝情報自体は変化せず、従来の遺伝子治療と比較して安全である。

Research Products

• [Journal Article] Synergistic Upregulation of Target Genes by TET1 and VP64 in the dCas9-SunTag Platform. (2020)
  • Author(s): Morita S, Horii T, Kimura M, Hatada I.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 5 Pages: 1574-1574
  • DOI: 10.3390/ijms21051574
  • Peer Reviewed / Open Access
• [Journal Article] Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome. (2020)
  • Author(s): Horii T, Morita S, Hino S, Kimura M, Hino Y, Kogo H, Nakao M & Hatada I
  • Journal Title: Genome Biology Volume: 21(1) Issue: 1 Pages: 77-77
  • DOI: 10.1186/s13059-020-01991-8
  • Peer Reviewed / Open Access
• [Journal Article] Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing. (2020)
  • Author(s): Hanzawa N, Hashimoto K, Yuan X, Kawahori K, Tsujimoto K, Hamaguchi M, Tanaka T, Nagaoka Y, Nishina H, Morita S, Hatada I, Yamada T, Ogawa Y.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 5181-5181
  • DOI: 10.1038/s41598-020-62035-6
  • Peer Reviewed / Open Access
• [Journal Article] Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells (2018)
  • Author(s): Gailhouste Luc、Liew Lee Chuen、Yasukawa Ken、Hatada Izuho、Tanaka Yasuhito、Nakagama Hitoshi、Ochiya Takahiro
  • Journal Title: Molecular Therapy Volume: 26 Issue: 7 Pages: 1840-1854
  • DOI: 10.1016/j.ymthe.2018.04.018
  • Peer Reviewed / Open Access
• [Journal Article] Editing of DNA Methylation Using dCas9-Peptide Repeat and scFv-TET1 Catalytic Domain Fusions (2018)
  • Author(s): Morita Sumiyo、Horii Takuro、Hatada Izuho
  • Journal Title: Methods Mol Biol. Volume: 1767 Pages: 419-428
  • DOI: 10.1007/978-1-4939-7774-1_23
  • ISBN: 9781493977734, 9781493977741
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. (2018)
  • Author(s): Gailhouste L, Liew LC, Hatada I, Nakagama H, Ochiya T.
  • Journal Title: Cell Death Dis. Volume: 9 Issue: 5 Pages: 468-468
  • DOI: 10.1038/s41419-018-0487-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ゲノム編集からエピゲノム編集まで (2019)
  • Author(s): 畑田出穂
  • Organizer: 第３０回日本医学会総会2019中部
  • Invited
• [Presentation] エピゲノム研究の新展開 (2019)
  • Author(s): 畑田 出穂
  • Organizer: 日本ゲノム編集学会 第4回大会
  • Invited
• [Presentation] ゲノム編集、エピゲノム編集によるモデルマウスの新展開 (2019)
  • Author(s): 畑田 出穂
  • Organizer: 第40回日本炎症・再生医学会
  • Invited
• [Presentation] Epigenome and genome editing of mammals (2018)
  • Author(s): Hatada i
  • Organizer: Genome Editing Towards Medicinal Applications
  • Int'l Joint Research / Invited
• [Presentation] Epigenome and genome editing of mammals (2018)
  • Author(s): 畑田出穂
  • Organizer: 第9回武田科学振興財団薬科学シンポジウム
  • Int'l Joint Research / Invited
• [Book] Editing of DNA Methylation Using dCas9-Peptide Repeat and scFv-TET1 Catalytic Domain Fusions. Morita S, Horii T, Hatada I. Methods Mol Biol. (2018)
  • Author(s): Morita S, Horii T, Hatada I.
  • Total Pages: 288
  • Publisher: Springer Nature
  • ISBN: 9781493977734