Selective modification of histone methylation using DNA binding-small molecules

• Project/Area Number: 26350977
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Chiba University
• Principal Investigator: Shinohara Ken-ichi 千葉大学, 大学院医学研究院, 特任助教 (70378561)
• Co-Investigator(Renkei-kenkyūsha): KANEDA Atsushi 千葉大学, 大学院医学研究院, 教授 (10313024) ; NEMOTO Tetsuhiro 千葉大学, 大学院薬学研究院, 特任助教 (80361450) ; SUZUKI Takayoshi 京都府立医科大学, 大学院医学研究科, 教授 (90372838) ; SUGIYAMA Hiroshi 京都大学, 大学院理学研究科, 教授 (50183843) ; NAGASE Hiroki 千葉県がんセンター, 研究所, 所長 (90322073) ; WATANABE Takayoshi 千葉県がんセンター, 研究所, 研究員 (60526060)
• Research Collaborator: YODA Natsumi ; FUKUYO Masaki ; TAKANE Kiyoko ; FUJIWARA Kyoko ; KITA Kazuko ; FUKUDA Noboru
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ピロール・イミダゾール・ポリアミド / 核酸化学 / 発現制御 / エピゲノム / ヒストンメチル化 / DNA配列認識 / エピゲノム制御 / ピロール・イミダゾールポリアミド / ピロール-イミダゾールポリアミド / エピジェネティクス

Outline of Final Research Achievements

Aberrant DNA methylation and histone modification cause major epigenetic changes and have been implicated in cancer growth. While drugs for epigenome such as SAHA and decitabine can be available for cancer treatment, site-specific modification of epigenome is now requested to be technically achieved. Pyrrole-imidazole polyamides are small molecules that can be designed to recognize and bind to particular DNA sequences. In this study, we synthesized PIP-LSD1 inhibitor conjugates and investigated whether the conjugates show site-selective changing of histone methylation. The results in this study indicate that PIP-inhibitor conjugates induced histone methylation where single inhibitor could not change. In addition, it is shown that PIP can act as sequence-specific antagonists of CpG methylation in living cells.

Research Products

• [Journal Article] Synthesis of Pyrrole-Imidazole Polyamide Oligomers Based on a Copper-Catalyzed Cross-Coupling Strategy. (2017)
  • Author(s): Shiga N, Takayanagi S, Muramoto R, Murakami T, Qin R, Suzuki Y, Shinohara K, Kaneda A, Nemoto T.
  • Journal Title: Bioorg Med Chem Lett, Volume: 27 Issue: 10 Pages: 2197-2200
  • DOI: 10.1016/j.bmcl.2017.03.052
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ゲノム領域選択的なエピゲノム制御アプローチ (2017)
  • Author(s): 篠原憲一、金田篤志
  • Journal Title: Medical Science Digest Volume: 43 Pages: 116-121
• [Journal Article] Platinum-Catalyzed Friedel-Crafts-Type C–H Coupling–Allylic Amination Cascade to Synthesize 3,4-Fused Tricyclic Indoles (2016)
  • Author(s): Yuta Suzuki, Yuito Tanaka, Shun-ichi Nakano, Kousuke Dodo, Natsumi Yoda, Ken-ichi Shinohara, Kazuko Kita, Atushi Kaneda, Mikiko Sodeoka, Yasumasa Hamada, and Tetsuhiro Nemoto
  • Journal Title: Chem. Eur. J. Volume: 22 Issue: 13 Pages: 4418-4421
  • DOI: 10.1002/chem.201600375
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Double beta-alanine substitutions incorporated in 12-ring pyrrole-Imidazole Polyamides for lengthened DNA minor groove recognition. (2016)
  • Author(s): Watanabe T, Shinohara K, Shinozaki Y, Uekusa S, Wang X, Koshikawa N, Hiraoka K, Inoue T, Lin J, Bando T, Sugiyama H and Nagase H.
  • Journal Title: Advanced Techniques in Biology & Medicine. Volume: 4 Issue: 02 Pages: 175-175
  • DOI: 10.4172/2379-1764.1000175
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inhibition of DNA methylation at the MLH1 promoter region using pyrrole-imidazole polyamide. (2016)
  • Author(s): Shinohara K, Yoda N, Takane K, Watanabe T, Fukuyo M, Fujiwara K, Kita K, Nagase H, Nemoto T, Kaneda A.
  • Journal Title: ACS Omega Volume: 1 Issue: 6 Pages: 1164-1172
  • DOI: 10.1021/acsomega.6b00229
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modulation of the EMT/MET Process by Pyrrole-Imidazole Polyamide Targeting Human Transforming Growth Factor-β1. (2015)
  • Author(s): Saito, K.; Fukuda, N.; Shinohara, K.; Masuhiro, Y.; Hanazawa, S.; Matsuda, H.; Fujiwara, K.; Ueno, T.; Soma, M.
  • Journal Title: Int. J. Biochem. Cell Biol. Volume: 66 Pages: 112-20
  • DOI: 10.1016/j.biocel.2015.07.011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Silencing of RUNX2 enhances gemcitabine sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the stimulation of TAp63-mediated cell death. (2015)
  • Author(s): Sugimoto H, Nakamura M, Yoda H, Hiraoka K, Shinohara K, Sang M, Fujiwara K, Shimozato O, Nagase H, Ozaki T.
  • Journal Title: Cell Death Discovery Volume: 6 Issue: 10 Pages: e1914-e1914
  • DOI: 10.1038/cddis.2015.242
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of KRAS Codon 12 Mutants Using a Novel DNA-alkylating Pyrrole-imidazole Polyamide Conjugate (2015)
  • Author(s): Hiraoka, K.; Inoue, T.; Taylor, R. D.; Watanabe, T.; Koshikawa, N.; Yoda, H.; Shinohara, K.; Takatori, A.; Sugimoto, K.; Maru, Y.; Denda, T.; Fujiwara, K.; Balmain, A.; Ozaki, T.; Bando, T.; Sugiyama, H.; Nagase, H.
  • Journal Title: Nature. Comm. Volume: in press
  • NAID: 120006460100
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate. (2014)
  • Author(s): Hiraoka K, Inoue T, Taylor RD, Watanabe T, Koshikawa N, Yoda H, Shinohara K, Takatori A, Sugimoto H, Maru Y, Denda T, Fujiwara K, Balmain A, Ozaki T, Bando T, Sugiyama H, Nagase H.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6706-6706
  • DOI: 10.1038/ncomms7706
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] DNA結合小分子を用いた選択的DNAメチル化阻害 (2016)
  • Author(s): 篠原憲一
  • Organizer: 日本ケミカルバイオロジー学会 第11回年会
  • Place of Presentation: 京都テルサ テルサホール（京都府・京都市）
  • Year and Date: 2016-06-15
• [Presentation] DNA配列認識小分子によるエピゲノム制御 (2015)
  • Author(s): 篠原憲一, 依田夏美, 渡部隆義, 永瀬浩喜, 金田篤志
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県・神戸市中央区）
  • Year and Date: 2015-12-01
• [Patent(Industrial Property Rights)] 配列特異的で設計可能な標的遺伝子の転写抑制阻害剤およびこれを含む組成物並び にその使用 (2017)
  • Inventor(s): 金田篤志、篠原憲一、根本哲宏
  • Industrial Property Rights Holder: 金田篤志、篠原憲一、根本哲宏
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-02-01
  • Overseas
• [Patent(Industrial Property Rights)] 遷移金属触媒反応を利用した 3,4 位中員環縮環 3-アルキリデンインドリ ン類、および 3,4 位中員環縮インドール類の合成法 (2016)
  • Inventor(s): 根本哲宏、濱田康正、鈴木雄太、仲野駿一、篠原憲一、金田篤志、他
  • Industrial Property Rights Holder: 根本哲宏、濱田康正、鈴木雄太、仲野駿一、篠原憲一、金田篤志、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-08-12