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Epigenetic memory in neural stem cells establishing individuality

Planned Research

Project AreaIntegrative research toward elucidation of generative brain systems for individuality
Project/Area Number 16H06527
Research Category

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

Allocation TypeSingle-year Grants
Review Section Complex systems
Research InstitutionKyushu University

Principal Investigator

Nakashima Kinichi  九州大学, 医学研究院, 教授 (80302892)

Co-Investigator(Kenkyū-buntansha) 今村 拓也  広島大学, 統合生命科学研究科(理), 教授 (90390682)
Project Period (FY) 2016-06-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥141,570,000 (Direct Cost: ¥108,900,000、Indirect Cost: ¥32,670,000)
Fiscal Year 2020: ¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000)
Fiscal Year 2019: ¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000)
Fiscal Year 2018: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000)
Fiscal Year 2017: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000)
Fiscal Year 2016: ¥48,750,000 (Direct Cost: ¥37,500,000、Indirect Cost: ¥11,250,000)
Keywords神経科学 / エピゲノム / 神経幹細胞 / 個性 / ダイレクトリプログラミング / てんかん / 脳梗塞 / ミクログリア / けいれん / Cxcr4
Outline of Final Research Achievements

It is important to consider the concept of epigenetics for development of the individuality. By focusing on the property of neural stem/progenitor cells (NS/PCs) residing in the adult hippocampus, we identified the mechanism of increased seizure sensitivity in prenatally HDAC inhibitor VPA-exposed adult mice. Furthermore, we found that voluntary exercise can overcome the adverse effects through normalizing VPA-induced transcriptome alterations in NS/PCs.
We also elucidated the mechanism whereby a transcription factor NeuroD1 converts microglia into induced neuronal (iN) cells accompanied by global remodeling of microglial epigenetic signature. Furthermore, iN cells were functionally integrated into brain circuits through synaptic connections with other neurons like endogenous neurons. These findings bring us one step closer to developing therapeutic strategies for nerve injury and disease by reprogramming microglia that accumulate at lesion sites into neurons.

Academic Significance and Societal Importance of the Research Achievements

個性創発にエピジェネティック修飾が関与すると同時に、自発的運動によりけいれん感受性増大という「負の個性」を完全できることを示した。また脳内の非ニューロン細胞をニューロンへと変換しうるとともに、それを利用した新規脳梗塞治療法を開発した。これらは、種々の神経疾患における治療法開発への応用が期待される。

Report

(6 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (41 results)

All 2021 2020 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (15 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 15 results,  Open Access: 10 results) Presentation (19 results) (of which Int'l Joint Research: 8 results,  Invited: 11 results) Remarks (5 results)

  • [Int'l Joint Research] USCD(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] UT Southwestern Medical Center(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] SoxE group transcription factor Sox8 promotes astrocytic differentiation of neural stem/precursor cells downstream of Nfia2021

    • Author(s)
      Takouda J., Katada S., Imamura T. and Nakashima K.
    • Journal Title

      Pharmacol Res Perspect

      Volume: -

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling2021

    • Author(s)
      Nakashima H., Tsujimura K., Irie K., Imamura T., Trujillo CA., Ishizu M., Uesaka M., Pan M., Noguchi H., Okada K., Aoyagi K., Andoh-Noda T., Okano H., Murotri AR., Nakashima K.
    • Journal Title

      Cell Rep

      Volume: -

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice2019

    • Author(s)
      Saito Hirokatsu、Hara Kenshiro、Tominaga Takashi、Nakashima Kinichi、Tanemura Kentaro
    • Journal Title

      Journal of Applied Toxicology

      Volume: 39 Issue: 12 Pages: 1651-1662

    • DOI

      10.1002/jat.3882

    • NAID

      130007898356

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Suppressor of fused controls perinatal expansion and quiescence of future dentate adult neural stem cells2019

    • Author(s)
      Noguchi Hirofumi、Castillo Jesse Garcia、Nakashima Kinichi、Pleasure Samuel J
    • Journal Title

      eLife

      Volume: 8

    • DOI

      10.7554/elife.42918

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion.2019

    • Author(s)
      Matsuda T, Irie T, Katsurabayashi S, Hayashi Y, Nagai T, Hamazaki N, Adefuin AMD, Miura F, Ito T, Kimura H, Shirahige K, Takeda T, Iwasaki K, Imamura T, Nakashima K.
    • Journal Title

      Neuron

      Volume: 101 (3) Issue: 3 Pages: 472-485

    • DOI

      10.1016/j.neuron.2018.12.010

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury.2018

    • Author(s)
      Nakashima H, Tsujimura K, Irie K, Ishizu M, Pan M, Kameda T, Nakashima K:
    • Journal Title

      Neurosci Res

      Volume: - Pages: 63-70

    • DOI

      10.1016/j.neures.2018.03.004

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury.2018

    • Author(s)
      Uezono N, Zhu Y, Y, Matsuda T,Nakajo M, Abematsu M, Setoguchi T, Mori S, Takahashi HK, Komiya S, Nishibori M, Nakashima K:
    • Journal Title

      Stem Cells

      Volume: - Issue: 5 Pages: 0-0

    • DOI

      10.1002/stem.2802

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice.2018

    • Author(s)
      Sakai A, Matsuda T, Doi H, Nagaishi Y, Kato K, Nakashima K
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: - Issue: 16 Pages: 4270-4275

    • DOI

      10.1073/pnas.1716479115

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] HMGB2 expression is associated with transition from a quiescent to an activated state of adult neural stem cells.2018

    • Author(s)
      Kimura A, Matsuda T, Sakai A, Murao N, Nakashima K
    • Journal Title

      Dev Dyn

      Volume: 247 Issue: 1 Pages: 229-238

    • DOI

      10.1002/dvdy.24559

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neural stem cell therapy aiming at better functional recovery after spinal cord injury2018

    • Author(s)
      Zhu Y, Uezono N, Yasui T, Nakashima K
    • Journal Title

      Dev Dyn

      Volume: 247 Issue: 1 Pages: 75-84

    • DOI

      10.1002/dvdy.24558

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synergistic induction of astrocytic differentiation by factors secreted from meninges in the mouse developing brain.2017

    • Author(s)
      Kawamura Y, Katada S, Noguchi H, Yamamoto H, Sanosaka T, Iihara K, Nakashima K
    • Journal Title

      FEBS lett

      Volume: 59 Issue: 22 Pages: 3709-3720

    • DOI

      10.1002/1873-3468.12881

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA Methylome Analysis Identifies Transcription Factor-Based Epigenomic Signatures of Multilineage Competence in Neural Stem/Progenitor Cells.2017

    • Author(s)
      Sanosaka T, Imamura T, Hamazaki N, Chai M, Igarashi K, Ideta-Otsuka M, Miura F, Ito T, Fujii N, Ikeo K, Nakashima K
    • Journal Title

      Cell Rep

      Volume: 20 Issue: 12 Pages: 2992-3003

    • DOI

      10.1016/j.celrep.2017.08.086

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Emerging mechanisms underlying astrogenesis in the developing mammalian brain2017

    • Author(s)
      Takouda J, Katada S, Nakashima K
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 93 Issue: 6 Pages: 386-398

    • DOI

      10.2183/pjab.93.024

    • NAID

      130005696812

    • ISSN
      0386-2208, 1349-2896
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia epigenetically confers astrocytic differentiation potential on human pluripotent cell-derived neural precursor cells.2017

    • Author(s)
      Yasui T, Uezono N, Nakashima H Noguchi H, Matsuda T, Noda-Andoh T, Okano H, Nakashima K:
    • Journal Title

      Stem Cell Reports

      Volume: 8 Issue: 6 Pages: 1743-1756

    • DOI

      10.1016/j.stemcr.2017.05.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NEUROD1 instructs neuronal conversion in non-reactive astrocytes.2017

    • Author(s)
      Brulet R, Matsuda T, Zhang L, Miranda C, Giacca M, Kaspar BK, Nakashima K, Hsieh J
    • Journal Title

      Stem Cell Reports

      Volume: 8 Issue: 6 Pages: 1506-1515

    • DOI

      10.1016/j.stemcr.2017.04.013

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ミクログリアからニューロンへの直接分化転換による脳梗塞治療法の開発2021

    • Author(s)
      中島欽一
    • Organizer
      STROKE2021
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] レット症候群原因因子MeCP2のマイクロRNAを介した神経幹細胞分化制御機構の解明2020

    • Author(s)
      中島欽一
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Artifitial neurogenesis in the adult central nervous system and it’s effect on functional recovery after injury2020

    • Author(s)
      Kinichi Nakashima
    • Organizer
      2nd Neuroepigenetics & Neuroepitranscriptomics
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Artificial generation of new neurons in adult central nervous systems2019

    • Author(s)
      Kinichi Nakashima
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Artificial Production of New Neurons in the Adult Central Nervous System2019

    • Author(s)
      Kinichi Nakashima
    • Organizer
      Cell&Gene Therapy Asia2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 転写因子NeuroD1によるミクログリアからニューロンへのダイレクトリプログラミングのメカニズム2019

    • Author(s)
      中島欽一
    • Organizer
      第91回日本遺伝学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 胎生期バルプロ酸曝露によるけいれん感受性増大のメカニズムとその改善法2019

    • Author(s)
      中島欽一
    • Organizer
      第46回日本毒性学会学術年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 転写因子 NeuroD1によるミクログリアからニューロンへの分化転換とそのメカニズム2018

    • Author(s)
      中島欽一
    • Organizer
      日本分子生物学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Prior inhibition of HMGB1 boots up human neural stem cell transplantation-mediated functional recovery after spinal cord injury2018

    • Author(s)
      Kinichi Nakashima
    • Organizer
      Korean Society for Brain and Neural Science
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Preservation of damaged tissue by prior inhibition of HMGB1 boosts human neural stem cell transplantation-mediated functional recovery after spinal cord injury2018

    • Author(s)
      Kinichi Nakashima
    • Organizer
      Cold Spring Harver Asia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 酸素濃度によるヒト神経幹細胞分化のエピジェネティック制御2018

    • Author(s)
      中島欽一
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 胎児期抗てんかん薬曝露マウスの成体でのけいれん感受性増加2017

    • Author(s)
      坂井淳彦、松田泰斗、中島欽一
    • Organizer
      第12回成体脳のニューロン新生懇談会
    • Place of Presentation
      滋賀医科大学
    • Year and Date
      2017-02-28
    • Related Report
      2016 Annual Research Report
  • [Presentation] 胎生期エピジェネティック撹乱による遅発性学習記憶障害とてんかん感受性増加のメカニズム2017

    • Author(s)
      中島欽一
    • Organizer
      第26回海馬と高次脳機能学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] DNA methylomes identifiy transcription factor-based epigenomic signatures for timed acquisition of differentiation competence in neural stem/progenitor cells towards neuronal and glia lineages2017

    • Author(s)
      今村拓也、佐野坂司、浜崎伸彦、Chai Muh Chyi、五十嵐勝秀、大塚まき、三浦史仁、伊藤隆司、藤井信之、池尾一穂、中島欽一
    • Organizer
      4th World Congress of Reproductive Biology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hypoxia epigenetically confers astrocytic differentiation potential on human pluripotent cell-derived neural precursor cells2017

    • Author(s)
      中島欽一
    • Organizer
      The 72nd Fujihara Seminar Molecular Mechanism of Molding and Disruption of the Epigenomes Underlying Cellular Community
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of non-coding RNA contributes to the complete cessation of cell proliferation of neuron-like cells2017

    • Author(s)
      今村拓也、山本直樹、阿形清和、中島欽一
    • Organizer
      第43回内藤コンファレンス
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] DNA Methylation Regulting Neuron-Glia Fate Switching of Neural Stem Cells2017

    • Author(s)
      中島欽一
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] エピゲノム変換を介したミクログリアからニューロンへの直接分化転換機構の解明2017

    • Author(s)
      松田泰斗、入江剛史、アデフィンアリア、中島欽一
    • Organizer
      第11回日本エピジェネティクス研究会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 胎児期抗てんかん薬曝露マウスの成体でのけいれん感受性増加2016

    • Author(s)
      坂井淳彦、松田泰斗、加藤聖子、中島欽一
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Remarks] 脳内に存在する免疫細胞から機能的な神経細胞の作製に成功

    • URL

      http://www.kyushu-u.ac.jp/ja/researches/view/307

    • Related Report
      2018 Annual Research Report
  • [Remarks] 妊婦への抗てんかん薬投与によって子どもはけいれんが起こりやすくなる!?

    • URL

      https://www.kyushu-u.ac.jp/ja/researches/view/234

    • Related Report
      2017 Annual Research Report
  • [Remarks] 脊髄損傷に対する神経幹細胞移植の治療効果を増強させる治療法の発見!

    • URL

      https://www.kyushu-u.ac.jp/ja/researches/view/225

    • Related Report
      2017 Annual Research Report
  • [Remarks] ほ乳類神経幹細胞が変化するメカニズムを明らかに

    • URL

      https://www.kyushu-u.ac.jp/ja/researches/view/171

    • Related Report
      2017 Annual Research Report
  • [Remarks] ヒトiPS細胞由来神経幹細胞の低酸素培養により、短期にアストロサイト分化を誘導

    • URL

      https://www.kyushu-u.ac.jp/ja/researches/view/131

    • Related Report
      2017 Annual Research Report

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Published: 2016-07-04   Modified: 2022-02-28  

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