Stage-specific roles of Notch signaling on induction of T cell development from hematopoietic progenitor cells

• Project/Area Number: 19H03692
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokai University
• Principal Investigator: HOSOKAWA HIROYUKI 東海大学, 医学部, 准教授 (60431756)
• Co-Investigator(Kenkyū-buntansha): 遠藤 裕介 公益財団法人かずさDNA研究所, 先端研究開発部, 室長 (80612192)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2023: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: Notchシグナル / T前駆細胞 / 造血幹細胞 / 転写制御ネットワーク / 発生段階特異的 / 転写因子ネットワーク / T細胞 / 細胞運命決定 / 転写因子 / 遺伝子発現制御 / 系列決定 / T細胞初期分化 / 細胞の運命決定 / プロテオミクス解析

Outline of Research at the Start

造血幹細胞からTリンパ球への分化に必須のNotchシグナルは、発生段階特異的に異なるターゲット遺伝子の発現を制御している。本研究では、ステージ特異的な、(1)Notch細胞内ドメイン会合分子の同定、(2)Notchノックアウト細胞のトランスクリプトーム解析、(3)NotchおよびRbpjのChIPシークエンス解析、を組み合わせることで、ステージ特異的な転写因子と外界からのシグナルであるNotchシグナルとの相互作用を包括的に理解し、造血幹細胞からTリンパ球への分化誘導においてNotchシグナルが発生段階特異的な機能を発揮する分子メカニズムの解明を目指す。

Outline of Final Research Achievements

One of the most important roles of the thymus is providing Notch ligands to the T progenitor cells. Stage-specific activities of Notch signaling in early T cell development are suggested by analysis of expression kinetics of individual Notch targets. To clarify stage-specific roles of Notch signaling, we employed the CRISPR/Cas9-mdeidated acute and stage-specific gene deletion system in pre- and post-commitment pro-T cells. Notch-regulated target genes before and after T-lineage commitment change dynamically, and we show that this partially reflects shifts in genome-wide DNA binding by Notch-IC/RBPJ complex.

Academic Significance and Societal Importance of the Research Achievements

本研究により、同じT前駆細胞でも発生段階によってNotchシグナルが制御する遺伝子群がダイナミックに変化することが明らかになった。Notchシグナル経路は、ショウジョウバエから哺乳類まで高度に保存されており、様々な器官の発生や細胞の運命決定を司る。一方で、Notch関連遺伝子の変異が様々なガン細胞で同定されており、その割合は全ガン細胞の5-10%と言われている。本研究をさらに発展させることで、Notchシグナル経路の異常がどのように細胞の腫瘍化を引き起こすのか、その分子メカニズムの解明に寄与することが期待される。

Research Products

• [Int'l Joint Research] カリフォルニア工科大学/イリノイ大学(米国)
• [Int'l Joint Research] カリフォルニア工科大学(米国)
• [Int'l Joint Research] Caltech(米国)
• [Int'l Joint Research] California Institute of Technology(米国)
• [Int'l Joint Research] カリフォルニア工科大学 生物学部門(米国)
• [Journal Article] Transcription factor Zbtb1 interacts with bridging factor Lmo2 and maintains the T-lineage differentiation capacity of lymphoid progenitor cells (2022)
  • Author(s): Koizumi Maria、Kama Yuichi、Hirano Ken-ichi、Endo Yusuke、Tanaka Tomoaki、Hozumi Katsuto、Hosokawa Hiroyuki
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 11 Pages: 102506-102506
  • DOI: 10.1016/j.jbc.2022.102506
  • Peer Reviewed / Open Access
• [Journal Article] Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis (2022)
  • Author(s): Fujimoto Masanori、Yokoyama Masataka、Kiuchi Masahiro、Hosokawa Hiroyuki、Nakayama Akitoshi、Hashimoto Naoko、Sakuma Ikki、Nagano Hidekazu、Yamagata Kazuyuki、Kudo Fujimi、Manabe Ichiro、Lee Eunyoung、Hatano Ryo、Onodera Atsushi、Hirahara Kiyoshi、Yokote Koutaro、Miki Takashi、Nakayama Toshinori、Tanaka Tomoaki
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 1-21
  • DOI: 10.1038/s41467-022-33171-6
  • Peer Reviewed / Open Access
• [Journal Article] GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma (2022)
  • Author(s): Suzuki Sawako、Venkatesh Divya、Kanda Hiroaki、Nakayama Akitoshi、Hosokawa Hiroyuki、Lee Eunyoung、Miki Takashi、Stockwell Brent R.、Yokote Koutaro、Tanaka Tomoaki、Prives Carol
  • Journal Title: Cancer Research Volume: 82 Issue: 18 Pages: 3209-3222
  • DOI: 10.1158/0008-5472.can-21-3914
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription factors regulate early T?cell development via redeployment of other factors (2021)
  • Author(s): Hosokawa Hiroyuki、Masuhara Kaori、Koizumi Maria
  • Journal Title: BioEssays Volume: 43 Issue: 5 Pages: 2000345-2000345
  • DOI: 10.1002/bies.202000345
  • Peer Reviewed
• [Journal Article] Notch signaling supports the appearance of follicular helper T cells in the Peyer's patches concomitantly with the reduction of regulatory T cells (2021)
  • Author(s): Yazawa M, Hosokawa H, Koizumi M, Hirano KI, Imai J, Hozumi K.
  • Journal Title: Int Immunol Volume: 33(9) Issue: 9 Pages: 469-478
  • DOI: 10.1093/intimm/dxab032
  • Peer Reviewed
• [Journal Article] Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells (2021)
  • Author(s): Hosokawa Hiroyuki、Koizumi Maria、Masuhara Kaori、Romero-Wolf Maile、Tanaka Tomoaki、Nakayama Toshinori、Rothenberg Ellen V.
  • Journal Title: Journal of Experimental Medicine Volume: 218(8) Issue: 8 Pages: 1-16
  • DOI: 10.1084/jem.20202648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LMO2 is essential to maintain the ability of progenitors to differentiate into T-cell lineage in mice (2021)
  • Author(s): Hirano K., Hosokawa H., Koizumi M., Endo Y., Yahata T., and Hozumi K
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.68227
  • Peer Reviewed / Open Access
• [Journal Article] Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium (2021)
  • Author(s): Hirano KI, Hosokawa H, Yahata T, Ando K, Tanaka M, Imai J, Yazawa M, Ohtsuka M, Negishi N, Habu S, Sato T, Hozumi K.
  • Journal Title: Front Immunol Volume: 13 Pages: 852427-852427
  • DOI: 10.3389/fimmu.2022.852427
  • Peer Reviewed / Open Access
• [Journal Article] Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching (2021)
  • Author(s): Shin Boyoung、Hosokawa Hiroyuki、Romero-Wolf Maile、Zhou Wen、Masuhara Kaori、Tobin Victoria R.、Levanon Ditsa、Groner Yoram、Rothenberg Ellen V.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 4
  • DOI: 10.1073/pnas.2019655118
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] How transcription factors drive choice of the T cell fate (2020)
  • Author(s): Hosokawa Hiroyuki、Rothenberg Ellen V.
  • Journal Title: Nature Reviews Immunology Volume: 21 Issue: 3 Pages: 162-176
  • DOI: 10.1038/s41577-020-00426-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AMBRA1 controls antigen-driven activation and proliferation of naive T cells (2020)
  • Author(s): Masuhara Kaori、Akatsuka Hisako、Tokusanai Mizuki、Li Chenyang、Iida Yumi、Okada Yoshinori、Suzuki Takahiro、Ohtsuka Masato、Inoue Ituro、Kimura Minoru、Hosokawa Hiroyuki、Hozumi Katsuto、Sato Takehito
  • Journal Title: International Immunology Volume: 33 Issue: 2 Pages: 107-118
  • DOI: 10.1093/intimm/dxaa063
  • Peer Reviewed
• [Journal Article] Notch2 complements Notch1 to mediate inductive signaling that initiates early T cell development (2020)
  • Author(s): Romero-Wolf Maile、Shin Boyoung、Zhou Wen、Koizumi Maria、Rothenberg Ellen V.、Hosokawa Hiroyuki
  • Journal Title: Journal of Cell Biology Volume: 219 Issue: 10
  • DOI: 10.1083/jcb.202005093
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cell type-specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells. (2020)
  • Author(s): Hosokawa H, Romero-Wolf M, Yang Q, Motomura Y, Levanon D, Groner Y, Moro K, Tanaka T, Rothenberg EV.
  • Journal Title: J Exp Med. Volume: 217(1) Issue: 1
  • DOI: 10.1084/jem.20190972
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Etv6 is a Tcf7- and Hes1-independent Notch target gene in the initiation of the T-lineage program (2024)
  • Author(s): Kenichi Hirano, Hiroyuki Hosokawa
  • Organizer: 第52回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] T細胞の発生を誘導するNotchシグナルの全容の解明 (2023)
  • Author(s): 平野健一、細川裕之
  • Organizer: 京都T cell conference
• [Presentation] Etv6 is a Tcf7- and Hes1-independent Notch target gene in the initiation of the T-lineage program (2023)
  • Author(s): Kenichi Hirano, Hiroyuki Hosokawa
  • Organizer: FASEB
  • Int'l Joint Research
• [Presentation] Notch signaling triggers T-lineage program via Tcf7-dependnent and -independent mechanisms (2022)
  • Author(s): Hiroyuki Hosokawa
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] Notch-dependent functional conversion of Runx1 at the initiation of T-lineage program (2022)
  • Author(s): Yuichi Kama, Hiroyuki Hosokawa
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Notch signaling triggers T-lineage program via Tcf7-dependnent and -independent mechanisms (2022)
  • Author(s): Ken-ichi Hirano, Hiroyuki Hosokawa
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] 初期T 細胞分化におけるPU.1 発現抑制メカニズムの解析 (2019)
  • Author(s): 細川裕之
  • Organizer: Kyoto T Cell Conference
• [Presentation] GATA3 and Runx1 repress PU.1 expression in early T cell development (2019)
  • Author(s): Hiroyuki Hosokawa, Ellen Rothenberg
  • Organizer: FASEB 'The Molecular Mechanisms of Immune Cell Development and Function Coference'
  • Int'l Joint Research
• [Presentation] T細胞の初期発生において転写因子PU.1はコファクターを再配置することにより遺伝子発現を制御する (2019)
  • Author(s): 細川裕之
  • Organizer: 日本分子生物学会総会
  • Invited
• [Presentation] GATA3 and Runx1 repress PU.1 expression in early T cell development (2019)
  • Author(s): Hiroyuki Hosokawa, Katsuto Hozumi, Ellen Rothenberg
  • Organizer: 日本免疫学会総会