Maintenance of T cell lineage commitment by DNA methylation

• Project/Area Number: 24689042
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Hematology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: TOMOKATSU Ikawa 独立行政法人理化学研究所, 統合生命医科学研究センター, 上級研究員 (60450392)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥26,260,000 (Direct Cost: ¥20,200,000、Indirect Cost: ¥6,060,000); Fiscal Year 2013: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2012: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
• Keywords: T細胞分化 / 運命決定 / Np95 / エピジェネティクス / DNAメチル化

Outline of Final Research Achievements

Epigenetic regulations, such as chromatin modification or DNA methylation play key roles in the maintenance of committed cells during differentiation. However, exact mechanisms are yet to be determined. Here we found that the Np95, which is shown to regulate the DNA methylation, is critical for early T cell differentiation. The T cell development in thymus of T-cell specific Np95-deficient mice was severely impaired at the early differentiation stage. Derepression of genes which are not normally expressed in thymic T cell progenitors were found. These results suggest that the Np95 is essential for the maintenance of T cell fate.

Research Products

• [Journal Article] Gene regulation. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells (2015)
  • Author(s): Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drabløs F, Lennartsson A, Rönnerblad M, Hrydziuszko O, Vitezic M, Freeman TC, Alhendi AM, Arner P, Axton R, Baillie JK, Beckhouse A, Bodega B, Briggs J, Brombacher F, Davis M, Detmar M, Ehrlund A, Endoh M, Eslami A, Fagiolini M, et al.
  • Journal Title: Science Volume: 347 Issue: 6225 Pages: 1010-1014
  • DOI: 10.1126/science.1259418
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The transcription repressors Bach2 and Bach1 promote B cell development by repressing myeloid program. (2014)
  • Author(s): Itoh-Nakadai A, Hikota R, Muto A, Kometani K, Matsui-Watanabe M, Sato Y, Kobayashi M, Nakamura A, Miura Y, Yano Y, Tashiro S, Sun J, Ikawa T, Ochiai K, Kurosaki T, and Igarashi K.
  • Journal Title: Nature Immunol. Volume: 15 Issue: 12 Pages: 1171-1180
  • DOI: 10.1038/ni.3024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. (2014)
  • Author(s): Hojyo S., T. Miyai, H. Fujishiro, M. Kawamura, T. Yasuda, A. Hijikata, B-H Bin, T. Irie, J. Tanaka, T. Atsumi, M. Murakami, M. Nakayama, O. Ohara, S. Himeno, H. Yoshida, H. Koseki, T. Ikawa, K. Mishima, and T. Fukada.
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 32 Pages: 11786-11791
  • DOI: 10.1073/pnas.1323557111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development (2014)
  • Author(s): Miyai T, Hojyo S, Ikawa T, Kawamura M, Irie T, Ogura H, Hijikata A, Bin BH, Yasuda T, Kitamura H, Nakayama M, Ohara O, Yoshida H, Koseki H, Mishima K, Fukada T
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 111 Issue: 32 Pages: 11780-11785
  • DOI: 10.1073/pnas.1323549111
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and epigenetic control of early lymphocyte development (2014)
  • Author(s): Ikawa T
  • Journal Title: Curr Top Microbiol Immunol. Volume: 381 Pages: 1-20
  • DOI: 10.1007/82_2014_370
  • ISBN: 9783319073941, 9783319073958
  • Open Access / Acknowledgement Compliant
• [Journal Article] The epigenetic regulator Uhrf1 facilitates proliferation and maturation of colonic regulatory T cells (2014)
  • Author(s): Yuuki Obata*, Yukihiro Furusawa*, Takaho A. Endo, Jafar Sharif, Daisuke Takahashi, Koji Atarashi, Manabu Nakayama, Satoshi Onawa, Yumiko Fujimura, Masumi Takahashi, Tomokatsu Ikawa, Takeshi Otsubo, Yuki I. Kawamura, Taeko Dohi, Shoji Tajima, Osamu Ohara, Kenya Honda, Shohei Hori, Hiroshi Ohno, Haruhiko Koseki and Koji Hase. 【* : 筆頭筆者】
  • Journal Title: Nature Immunology Volume: 15 Issue: 6 Pages: 571-579
  • DOI: 10.1038/ni.2886
  • Peer Reviewed / Open Access
• [Journal Article] A promoter-level mammalian expression atlas. (2014)
  • Author(s): Forrest, A.R.R., Kawaji, H., Rehli, M., Baillie, J.K, de Hoon, M.J.L., Haberle, V., Lassmann, T., Kulakovskiy, I.V., Lizio, M., Itoh, M., Andersson, R., Mungall, C. J.,et al.
  • Journal Title: Nature Volume: 507 Issue: 7493 Pages: 462-470
  • DOI: 10.1038/nature13182
  • Peer Reviewed / Open Access
• [Journal Article] Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells. (2013)
  • Author(s): Hoshii T, Kasada A, Hatakeyama T, Ohtani M, Tadokoro Y, Naka K, Ikenoue T, Ikawa T, Kawamoto H, Fehling HJ, Araki K, Yamamura K, Matsuda S, Hirao A
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 10 Pages: 3805-3810
  • DOI: 10.1073/pnas.1320265111
  • Peer Reviewed
• [Journal Article] MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors. (2013)
  • Author(s): Okuyama K, Ikawa T, Gentner B, Hozumi K, Harnprasopwat R, Lu J, Yamashita R, Ha D, Toyoshima T, Chanda B, Kawamata T, Yokoyama K, Wang S, Ando K, Lodish HF, Tojo A, Kawamoto H, Kotani A
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Issue: 33 Pages: 13410-13415
  • DOI: 10.1073/pnas.1220710110
  • Peer Reviewed
• [Journal Article] Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells (2013)
  • Author(s): Vizcardo, R
  • Journal Title: Cell Stem Cell Volume: 12 Issue: 1 Pages: 31-36
  • DOI: 10.1016/j.stem.2012.12.006
  • Peer Reviewed
• [Journal Article] Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM (2012)
  • Author(s): Isoda T, Takagi M, Piao J, Nakagama S,Sato M, Masuda K, Ikawa T, Azuma M, Morio T, Kawamoto H, Mizutani S
  • Journal Title: Blood Volume: 120(4) Issue: 4 Pages: 789-9
  • DOI: 10.1182/blood-2012-02-413195
  • Peer Reviewed
• [Journal Article] Runx1-Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1. (2012)
  • Author(s): Seo Wooseok
  • Journal Title: Journal of Experimental Medicine Volume: 209 Issue: 7 Pages: 1255-1262
  • DOI: 10.1084/jem.20112745
  • Peer Reviewed
• [Journal Article] E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin | locus. (2012)
  • Author(s): Sakamoto, S., ffakae, K., Anzai, Y., Murai, K., Tamaki, N., Miyazaki, M., Miyazaki, K., Romanow, W. J., Ikawa, T., Kitamura, D., Yanagihira, I., Minato, N., Murre, C., Agata, Y
  • Journal Title: J. Immunol Volume: 188 Issue: 11 Pages: 5547-5560
  • DOI: 10.4049/jimmunol.1002346
  • Peer Reviewed
• [Presentation] Gene regulatory network orchestrating B cell fate specification (2015)
  • Author(s): Tomokatsu Ikawa
  • Organizer: RIKEN EPIGENETICS in Kobe
  • Place of Presentation: 神戸市 RIKEN CDB
  • Year and Date: 2015-02-13
• [Presentation] Epigenetic maintenance of T cell identity by Polycomb-mediated suppression of Pax5 (2014)
  • Author(s): Tomokatsu Ikawa
  • Organizer: 日本免疫学会
  • Place of Presentation: 京都市 国立京都国際会館
  • Year and Date: 2014-12-11
• [Presentation] T細胞系列への運命決定とエピジェネティクス (2014)
  • Author(s): 伊川 友活
  • Organizer: LEGENDセミナー
  • Place of Presentation: 京都市 ホテルグランヴィア京都
  • Year and Date: 2014-12-09
  • Invited
• [Presentation] Maintenance of T cell identity by Polycomb group proteins (2014)
  • Author(s): Ikawa T
  • Organizer: France-Japan Immunology meeting
  • Place of Presentation: フランス カシス
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] Genetic and epigenetic control of early lymphocyte development (2014)
  • Author(s): Ikawa T
  • Organizer: Max Planck Institute seminar
  • Place of Presentation: ドイツ フライブルグ
  • Year and Date: 2014-10-20
  • Invited
• [Presentation] Polycomb group proteins Ring1A/B are required for the maintenance of T cell fate (2014)
  • Author(s): Ikawa T
  • Organizer: CSHL meeting
  • Place of Presentation: アメリカ コールドスプリングハーバー
  • Year and Date: 2014-04-22
• [Presentation] 細胞分化の研究に魅せられて (2014)
  • Author(s): 伊川 友活
  • Organizer: 新学術領域「細胞運命制御」若手の会
  • Place of Presentation: 浜松市 浜名湖ロイヤルホテル
  • Year and Date: 2014-04-22
  • Invited
• [Presentation] A genetic network during the T cell lineage specification. (2013)
  • Author(s): Tomokatsu Ikawa
  • Organizer: The 6th International Workshop of Kyoto T cell conference 2013.
  • Place of Presentation: 京都市
• [Presentation] Roles of Polycomb group proteins in the maintenance of T cell fate. (2013)
  • Author(s): Tomokatsu Ikawa
  • Organizer: 15th International Congress of Immunology.
  • Place of Presentation: イタリア ミラノ
• [Presentation] Epigenetic regulation in T cell lineage commitment. (2013)
  • Author(s): Tomokatsu Ikawa
  • Organizer: The 5th LJI & IMS-RCAI Joint Workshop.
  • Place of Presentation: 横浜市
  • Invited
• [Presentation] Maintenance of T cell identity by Polycomb group complexes. (2013)
  • Author(s): Tomokatsu Ikawa
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張市
• [Presentation] A novel system to clarify the gene regulatory networks in B cell lineage commitment. (2013)
  • Author(s): Miyai Tomohiro, Tomokatsu Ikawa
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張市
• [Presentation] Maintenance of T cell fate after the commitment to the T cell lineage (2012)
  • Author(s): Tomokatsu Ikawa
  • Organizer: 日本免疫学会
  • Place of Presentation: 神戸市
  • Year and Date: 2012-12-06
• [Presentation] Gene regulatory networks in T cell lineage specification (2012)
  • Author(s): Tomokatsu Ikawa
  • Organizer: FANTOM5 MEETING
  • Place of Presentation: 横浜市
  • Year and Date: 2012-10-31
• [Presentation] T細胞系列へ決定後の運命維持機構 (2012)
  • Author(s): 伊川 友活
  • Organizer: Kyoto T cell Conference
  • Place of Presentation: 京都市
  • Year and Date: 2012-07-06
• [Presentation] Induction of myelo-lymphoid stem cells by suppressing E-protein activities (2012)
  • Author(s): Tomokatsu Ikawa
  • Organizer: Gene expression & signaling in the immune system
  • Place of Presentation: 京都市
  • Year and Date: 2012-04-25