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B細胞系列への運命決定を制御する転写ネットワークの解明

Publicly Offered Research

Project AreaMolecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
Project/Area Number 25118732
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe Institute of Physical and Chemical Research

Principal Investigator

伊川 友活  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) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsB細胞分化 / 運命決定 / 転写因子 / エピジェネティクス / リンパ球
Outline of Annual Research Achievements

B細胞を含むすべての血液・免疫細胞は造血幹細胞から作られる。その過程で多能性の造血幹細胞は徐々に分化能が限定されていき、最終的にB細胞にしかなれない前駆細胞に運命決定される。E2A、EBF1、PAX5など様々な転写因子がB細胞への運命決定に関わっているが、詳細は明らかでない。特にこれらの転写因子同士がどのようなネットワークを形成し、B細胞への運命決定を制御しているのか不明である。申請者らは最近このB細胞への運命決定に必要な転写ネットワークを調べる新しい分化誘導系を開発した。
そこで本研究では、培養細胞の遺伝子発現を網羅的に解析し転写因子間ネットワークのモデルを構築することを目的とした。本年度は研究計画に基づき、多能前駆細胞株(iLS細胞)からB細胞系列へ分化誘導後の経時サンプルを用いて網羅的な遺伝子発現解析(RNA-seq)およびエピジェネティック解析(ChIP-seq)を行った。さらにこのデータを元にバイオインフォマティクス解析を行った。
RNA-seq解析から転写因子の発現パターンによっていくつかのクラスターに分けられることが明らかとなった。培養0.5~1時間で誘導される転写因子(Nfil3, Nr4aなど)、培養2~4時間で誘導される転写因子(Tead1, Sox9など)、更にその後に誘導される転写因子(Ebf1, Pax5など)が存在することが明らかとなった。すなわち、Ebf1やPax5などB細胞特異的転写因子が発現する以前に、転写因子群が一過的かつダイナミックに次々と誘導されることが明らかとなった。これらのいわば転写カスケードがB細胞への運命決定を制御していると考えられる。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (22 results)

All 2015 2014 2013

All Journal Article (10 results) (of which Peer Reviewed: 9 results,  Open Access: 8 results,  Acknowledgement Compliant: 4 results) Presentation (12 results) (of which Invited: 5 results)

  • [Journal Article] Gene regulation. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells2015

    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development2014

    • 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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic and epigenetic control of early lymphocyte development2014

    • Author(s)
      Ikawa T
    • Journal Title

      Curr Top Microbiol Immunol.

      Volume: 381 Pages: 1-20

    • DOI

      10.1007/82_2014_370

    • ISBN
      9783319073941, 9783319073958
    • Related Report
      2014 Annual Research Report
    • Open Access / Acknowledgement Compliant
  • [Journal Article] The epigenetic regulator Uhrf1 facilitates proliferation and maturation of colonic regulatory T cells2014

    • 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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An atlas of active enhancers across human cell types and tissues.2014

    • Author(s)
      Anderson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Collaborators(261) Enomoto H, etc.
    • Journal Title

      Nature

      Volume: 507 Issue: 7493 Pages: 455-461

    • DOI

      10.1038/nature12787

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • 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

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] Gene regulatory network orchestrating B cell fate specification2015

    • Author(s)
      Tomokatsu Ikawa
    • Organizer
      RIKEN EPIGENETICS in Kobe
    • Place of Presentation
      神戸市
    • Year and Date
      2015-02-13
    • Related Report
      2014 Annual Research Report
  • [Presentation] Epigenetic maintenance of T cell identity by Polycomb-mediated suppression of Pax52014

    • Author(s)
      Tomokatsu Ikawa
    • Organizer
      日本免疫学会
    • Place of Presentation
      京都市
    • Year and Date
      2014-12-11
    • Related Report
      2014 Annual Research Report
  • [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
    • Year and Date
      2014-12-09
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Maintenance of T cell identity by Polycomb group proteins2014

    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Genetic and epigenetic control of early lymphocyte development2014

    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Polycomb group proteins Ring1A/B are required for the maintenance of T cell fate2014

    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Year and Date
      2014-04-22
    • Related Report
      2014 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
    • Invited
  • [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
    • Related Report
      2013 Annual Research Report
  • [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
      千葉市
    • Related Report
      2013 Annual Research Report
  • [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
      千葉市
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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