Chromatin remodeling and Induction of pluripotency via Sox2/TBP complex

• Project/Area Number: 17H04044
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Nagasaki University
• Principal Investigator: ITO Takashi 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90306275)
• Co-Investigator(Kenkyū-buntansha): 中川 武弥 長崎大学, 医歯薬学総合研究科(医学系), 助教 (50363502) ; 米田 光宏 長崎大学, 医歯薬学総合研究科(医学系), 講師 (80508367) ; 今村 優子 長崎大学, 医歯薬学総合研究科(医学系), 特任研究員 (50610937)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: クロマチン / SOX2 / TBP / リプログラミング / 遺伝子転写 / エピジェネティクス / リモデリング

Outline of Final Research Achievements

It has been discovered that Reprogramming of somatic cells achieved by combination of the four transcription factors Oct4, Sox2, Klf4, and c-Myc. However detailed mechanisms of this reprograming remained to be clarified. Recently we identify unique SOX2 complex including stoichiometric amount of TBP without TAFs. SOX2/TBP Complex plays role in chromatin assembly. In addition, SOX2/TBP facilitated chromatin remodeling around promoter region of both RNA Pol II and Pol I, resulting in their transcriptional activation in vitro. Both SOX2 and TBP bound to core promoter or enhancer region of both RNA Pol II and Pol I. Knockdown of SOX2 or TBP resulted in decreased rDNA and OCT3/4 expression together with diminished their binding to core promoter and enhancer region in vivo. These results indicated unique complex including SOX2 and TBP plays a role both in Pol I and Pol II transcription.

Academic Significance and Societal Importance of the Research Achievements

Oct3/4, Sox2, Klf4, cMycによる分化細胞から多能性幹細胞へのリプログラミングは再生医学領域への応用が期待され社会的にもインパクトの大きい領域である。実際に細胞核内で引き起こされる現象にはまだまだ未知の部分が多い。今回の実験によりSox2/TBP Complexはクロマチン構造変換能を有することを明らかにし、リプログラミングとエピジェネティクスの接点を明らかにしていく上で重要な発見である。詳細な機能の解明によりリプログラミングを含む再生医学領域に貢献できると考える。

Research Products

• [Journal Article] miR-222 regulates proliferation of primary mouse hepatocytes in vitro. (2019)
  • Author(s): Higashi, M., Yoneda, M., Nakagawa, T., Ikeda, M., and Ito, T.
  • Journal Title: Biochem Biophys Res Commun Volume: 511 Issue: 3 Pages: 644-649
  • DOI: 10.1016/j.bbrc.2019.02.093
  • Peer Reviewed
• [Journal Article] Enhancer function regulated by combinations of transcription factors and cofactors (2018)
  • Author(s): Nakagawa Takeya、Yoneda Mitsuhiro、Higashi Miki、Ohkuma Yoshiaki、Ito Takashi
  • Journal Title: Genes to Cells Volume: 23 Issue: 10 Pages: 808-821
  • DOI: 10.1111/gtc.12634
  • Peer Reviewed
• [Journal Article] MicroRNA-3662 expression correlates with antiviral drug resistance in adult T-cell leukemia/lymphoma cells. (2018)
  • Author(s): Yasui K, Izumida M, Nakagawa T, Kubo Y, Hayashi H, Ito T, Ikeda H, Matsuyama T
  • Journal Title: Biochem Biophys Res Commun Volume: 印刷中 Issue: 4 Pages: 833-837
  • DOI: 10.1016/j.bbrc.2018.04.159
  • Peer Reviewed / Open Access
• [Journal Article] Defects in centromeric/pericentromeric histone H2A T120 phosphorylation by hBUB1 cause chromosome missegregation producing multinucleated cells (2018)
  • Author(s): Maeda Katsutoshi、Yoneda Mitsuhiro、Nakagawa Takeya、Ikeda Kazuhiro、Higashi Miki、Nakagawa Kaori、Miyakoda Mana、Yui Katsuyuki、Oda Hiroaki、Inoue Satoshi、Ito Takashi
  • Journal Title: Genes to Cells Volume: 23 Issue: 10 Pages: 828-838
  • DOI: 10.1111/gtc.12630
  • Peer Reviewed
• [Journal Article] The MAP3K2-ERK5 pathway upregulates cyclin D1 expression through histone H2A (Thr120) phosphorylation by VRK1. (2018)
  • Author(s): Kato, M., Yoneda, M., Takeshima, Y., Amatya, V.J., Higashi, M., Nakagawa, T., and Ito, T.
  • Journal Title: Acta Medica Nagasakiensia Volume: 62 Pages: 15-26
  • NAID: 130007683941
  • Peer Reviewed
• [Journal Article] Chromosomal Abnormalities in Human Lymphocytes after Computed Tomography Scan Procedure (2018)
  • Author(s): Shi L, Fujioka K, Sakurai-Ozato N, Fukumoto W, Satoh K, Sun J, Awazu A, Tanaka K, Ishida M, Ishida T, Nakano Y, Kihara Y, Hayes CN, Aikata H, Chayama K, Ito T, Awai K, Tashiro S
  • Journal Title: Radiation Research Volume: 190 Issue: 4 Pages: 424-432
  • DOI: 10.1667/rr14976.1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mediator cyclin-dependent kinases upregulate transcription of inflammatory genes in cooperation with NF-κB and C/EBPβ on stimulation of Toll-like receptor 9. (2017)
  • Author(s): Yamamoto, S., Hagihara, T., Horiuchi, Y., Okui, A., Wani, S., Yoshida, T., Inoue, T., Tanaka, A., Ito, T., Hirose, Y., and Ohkuma, Y.
  • Journal Title: GENES TO CELLS Volume: 22 Issue: 3 Pages: 265-276
  • DOI: 10.1111/gtc.12475
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Histone H2A Thr 120 phosphorylation results in cancer via up regulation of Cyclin D1 (2018)
  • Author(s): Takashi Ito
  • Organizer: 第41回日本分子生物学会年会
• [Remarks] 長崎大学医学部生化学
  • URL: http://www.med.nagasaki-u.ac.jp/biochem/