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新規ポリコーム群複合体による造血制御とその造血器腫瘍における機能解析

Research Project

Project/Area Number 14J40042
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Hematology
Research InstitutionChiba University

Principal Investigator

中島 やえ子  千葉大学, 医学研究院, 特別研究員(RPD)

Project Period (FY) 2014-04-25 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsポリコーム群遺伝子 / エピジェネティクス / Pcgf1 / Bcor / ポリコーム / 造血幹細胞分化 / Non-canonical PRC1
Outline of Annual Research Achievements

これまでにPcgf1遺伝子は造血幹細胞の分化決定において骨髄球系分化の抑制因子として機能していることが示唆されている。Pcgf1遺伝子欠損マウスでは骨髄球関連遺伝子群の発現が造血幹細胞・多能性前駆細胞において異所性に活性化していること、特に顆粒球分化において重要な役割を果たすC/EBPα, C/EBPε遺伝子の発現が脱抑制していることが明らかになった。主成分分析では、Pcgf1欠損多能性前駆細胞(MPP)が骨髄球前駆細胞(GMP、PreGM)様の発現パターンを示すことが示された。また、Pcgf1欠損造血幹細胞を骨髄球分化条件下で培養したところ、骨髄球増殖活性の顕著な増強を示した。このことは定常状態においてはPcgf1が造血幹細胞・多能性前駆細胞の骨髄球分化決定および骨髄球系細胞増殖の抑制因子として機能していることを示唆する。
一方、Pcgf1と同様にPRC1.1の構成因子であるBcor遺伝子欠損マウスは300日までに約半数が急性Tリンパ芽球性白血病 (T-ALL) を発症することが明らかになった。T-ALL腫瘍細胞の遺伝子発現解析を行ったところ、T-ALLにおける重要なNotch標的遺伝子として知られるc-Myc、さらにはc-Myc標的遺伝子群の発現が亢進していることが明らかとなった。BcorはCD4+CD8+胸腺T前駆細胞においてc-Mycプロモーターに結合すること、Bcl6遺伝子欠損胸腺細胞も類似の遺伝子発現プロファイルを示すことから、BcorはBcl6と協調してc-MycをはじめとしたNotch標的遺伝子の発現を抑制的に制御することで、がん抑制遺伝子として機能していることが明らかとなった(Tanaka*, Nakajima-Takagi* et al., J Exp Med改定中 *Equal contribution)

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (12 results)

All 2016 2015 2014

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (7 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells2016

    • Author(s)
      Si S, Nakajima-Takagi Y, Aoyama K, Oshima M, Saraya A, Sugishita H, Nakayama M, Ishikura T, Koseki H, Iwama A
    • Journal Title

      PLoS One

      Volume: 11 Issue: 5 Pages: e0154561-e0154561

    • DOI

      10.1371/journal.pone.0154561

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice.2015

    • Author(s)
      Wang C, Oshima M, Sashida G, Tomioka T, Hasegawa N, Mochizuki-Kashio M, Nakajima-Takagi Y, Kusunoki Y, Kyoizumi S, Imai K, Nakachi K, Iwama A.
    • Journal Title

      PLoS One

      Volume: 10 Issue: 7 Pages: e0132041-e0132041

    • DOI

      10.1371/journal.pone.0132041

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Heme-mediated inhibition of Bach1 regulates the liver specificity and transience of the Nrf2-dependent induction of zebrafish heme oxygenase 1.2015

    • Author(s)
      Fuse, Y., Nakajima, H., Nakajima-Takagi, Y., Nakajima, O. and Kobayashi, M.
    • Journal Title

      Genes Cells

      Volume: 20 Issue: 7 Pages: 590-600

    • DOI

      10.1111/gtc.12249

    • NAID

      120007135764

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1.2015

    • Author(s)
      Matsushita K, Kitamura K, Rahmutulla B, Tanaka N, Ishige T, Satoh M, Hoshino T, Miyagi S, Mori T, Itoga S, Shimada H, Tomonaga T, Kito M, Nakajima-Takagi Y, Kubo S, Nakaseko C, Hatano M, Miki T, Matsuo M, Fukuyo M, Kaneda A, Iwama A, Nomura F.
    • Journal Title

      Oncotarget

      Volume: 6 Pages: 5102-5117

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development.2014

    • Author(s)
      Mishima Y, Wang C, Miyagi S, Saraya A, Hosokawa H, Mochizuki-Kashio M, Nakajima-Takagi Y, Koide S, Negishi M, Sashida G, Naito T, Ishikura T, Onodera A, Nakayama T, Tenen DG, Yamaguchi N, Koseki H, Taniuchi I, Iwama A.
    • Journal Title

      Nature Communications

      Volume: 18 Issue: 1 Pages: 5872-5882

    • DOI

      10.1038/ncomms6872

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of the polycomb-group protein Pcgf1 in the lineage commitment of hematopoietic stem cells2016

    • Author(s)
      Yaeko Nakajima-Takagi, Motohiko Oshima, Sha Si, Atsunori Saraya, Tomokatsu Ikawa, Junichiro Takano, Haruhiko Koseki, and Atsushi Iwama
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      パシフィコ横浜(神奈川県, 横浜市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] Concurrent Deletion of Bcor and Tet2 Causes Lethal Myelodysplasia.2016

    • Author(s)
      Shiro Tara, Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Motohiko Oshima, Atsunori Saraya, Haruhiko Koseki, Atsushi Iwama.
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      パシフィコ横浜(神奈川県, 横浜市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] Role of the polycomb group protein Pcgf1 in hematopoietic system.2015

    • Author(s)
      Yaeko Nakajima-Takagi, Motohiko Oshima, Sha Si, Atsunori Saraya, Haruhiko Koseki, and Atsushi Iwama.
    • Organizer
      第77回日本血液学会学術集会
    • Place of Presentation
      石川県立音楽堂(石川県, 金沢市)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of polycomb group protein Pcgf5 in hematopoietic system.2015

    • Author(s)
      Sha Si, Yaeko Nakajima-Takagi, Motohiko Oshima, Kazumasa Aoyama, Atsunori Saraya, Haruhiko Koseki and Atsushi Iwama
    • Organizer
      第77回日本血液学会学術集会
    • Place of Presentation
      石川県立音楽堂(石川県, 金沢市)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of the polycomb gene Bcor in hematopoiesis.2015

    • Author(s)
      Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Motohiko Oshima, Atsunori Saraya, Shiro Tara, Sha Si, Hirohito Sone, Haruhiko Koseki and Atsushi Iwama
    • Organizer
      第44回国際血液・幹細胞学会議(ISEH)
    • Place of Presentation
      国立京都国際会館(京都府, 京都市)
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 56th American Society of Hematology Annual Meeting2014

    • Author(s)
      Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Si Sha, Haruhiko Koseki and Atsushi Iwama
    • Organizer
      Role of the polycomb gene Bcor in hematopoiesis.
    • Place of Presentation
      San Francisco, United States of America
    • Year and Date
      2014-12-06 – 2014-12-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] Role of the polycomb gene Bcor in hematopoiesis.2014

    • Author(s)
      Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Si Sha, Haruhiko Koseki and Atsushi Iwama
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪国際会議場(大阪府・大阪市)
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Annual Research Report

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Published: 2015-01-22   Modified: 2024-03-26  

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