Regulation mechanisms of hematopoietic transcription factor RUNX1 through the transcription network analyses

• Project/Area Number: 16K09857
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: TADAGAKI KENJIRO 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30416268)
• Co-Investigator(Kenkyū-buntansha): 奥田 司 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30291587)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 造血幹細胞 / 転写因子 / RUNX1 / 標的遺伝子 / Runx1

Outline of Final Research Achievements

To understand the molecular mechanism of the regulation of hematopoietic stem cells, we focused on the identification of the novel transcriptional targets of hematopoietic transcription factor RUNX1. Although many target genes have so far been identified, a number of important targets should still remain to be elucidated. We have selected three candidate genes through array-analysis of the RUNX1-deficient murine ES cells that have been described for hematopoietic regulation. We found that RUNX1 regulated the promoter activity of all these three genes detected by luciferase reporter assay experiments. ChIP assay showed that RUNX1 bound to the RUNX1-binding sequence(s) in the cis-regulatory sequences of the two candidate genes of the three. In addition, the message levels of these genes were regulated depending on the RUNX1 status in the cell-level experiments. Thus, the two genes of the three candidate genes should be the novel transcriptional target genes of RUNX1.

Academic Significance and Societal Importance of the Research Achievements

RUNX1は造血幹細胞の発生制御のみならず、血小板産生やＴ細胞分化においても中心となる働きを担う転写因子である。本研究によって、これまで知られていなかった２つの標的遺伝子を新規に特定することに成功した。これはRUNX1作用の分子メカニズムの理解を一歩進めるものと考えている。また、これらの分子はいずれも造血・免疫系に関与することが知られていることから、今後、これらの遺伝子群の生物作用の詳細や、RUNX1との機能協調の詳細解析へと研究が展開するものと期待される。こうした研究によって、造血の分子メカニズムの詳細解明やRUNX1機能異常が関わるヒト疾患の新規治療法の開発に貢献することが期待される。

Research Products

• [Journal Article] The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development. (2018)
  • Author(s): Wojciech S, Ahmad R, Belaid-Choucair Z, Journe AS, Gallet S, Dam J, Daulat A, Ndiaye-Lobry D, Lahuna O, Karamitri A, Guillaume JL, Do Cruzeiro M, Guillonneau F, Saade A, Clement N, Courivaud T, Kaabi N, Tadagaki K, Delagrange P, Prevot V, Hermine O, Prunier C, Jockers R.
  • Journal Title: Nature Communications Volume: 9 (1) Issue: 1 Pages: 1216-1216
  • DOI: 10.1038/s41467-018-03609-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50. (2017)
  • Author(s): Clement N, Renault N, Guillaume JL, Cecon E, Journe AS, Laurent X, Tadagaki K, Coge F, Gohier A, Delagrange P, Chavatte P, Jockers R.
  • Journal Title: British Journal of Pharmacology Volume: - Issue: 16 Pages: 3281-3297
  • DOI: 10.1111/bph.14029
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Systematic protein-protein interaction mapping for clinically relevant human GPCRs. (2017)
  • Author(s): Sokolina K, Kittanakom S, Snider J, Kotlyar M, Maurice P, Gandia J, Benleulmi-Chaachoua A, Tadagaki K, Oishi A, Wong V, Malty RH, Deineko V, Aoki H, Amin S, Yao Z, Morato X, Otasek D, Kobayashi H, Menendez J, Auerbach D, Angers S, Przulj N, Bouvier M, Babu M, Ciruela F, Jockers R, Jurisica I, Stagljar I.
  • Journal Title: Molecular Systems Biology Volume: 13(3) Issue: 3
  • DOI: 10.15252/msb.20167430
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] SWI/SNFクロマチンリモデリング因子と造血系転写因子の機能調節 (2019)
  • Author(s): 桒原康道、近藤則子、忠垣憲次郎、山崎健太、吉田達士、奥田司
  • Organizer: 第２３回造血器腫瘍研究会
• [Presentation] A novel transcription factor RUNX1. (2018)
  • Author(s): Tatsushi Yoshida, Kenta Yamasaki, Kenjiro Tadagaki, Yasumichi Kuwahara, Noriko Kondo, Akifumi Matsumoto, Toshiyuki Sakai, Tsukasa Okuda.
  • Organizer: 第９１回日本生化学会
• [Presentation] Functional interaction between SWI/SNF complex and a hematopoietic transcription factor in malignant rhabdoid tumor. (2018)
  • Author(s): Yasumichi Kuwahara, Tatsushi Yoshida, Kenjiro Tadagaki, Tsukasa Okuda.
  • Organizer: 第７７回日本癌学会
• [Presentation] Analysis of a novel candidate target gene of the hematopoietic transcription factor RUNX1 (AML1). (2018)
  • Author(s): Kenjiro Tadagaki, Kenta Yamasaki, Noriko Kondo, Yasumichi Kuwahara, Tatsushi Yoshida, Tsukasa Okuda.
  • Organizer: 第８０回日本血液学会
• [Presentation] 急性骨髄性白血病におけるRUNX1新規標的遺伝子の同定 (2018)
  • Author(s): 松本晃典、吉田達士、山崎健太、忠垣憲次郎、桒原康道、近藤則子、奥田司
  • Organizer: 平成３０年度第８回４大学連携研究フォーラム
• [Presentation] 造血関連転写因子RUNX1(AML1)の新規転写標的候補遺伝子の探索 (2018)
  • Author(s): 忠垣憲次郎、山崎健太、近藤則子、桒原康通、吉田達士、奥田司
  • Organizer: 第４１回日本分子生物学会
• [Presentation] クロマチンリモデリング因子SNF5と細胞の腫瘍化 (2018)
  • Author(s): 桒原康道、近藤則子、忠垣憲次郎、山崎健太、吉田達士、奥田司
  • Organizer: 第２２回造血器腫瘍研究会
• [Presentation] RUNX1によるTRAIL遺伝子の転写制御機構 (2017)
  • Author(s): 吉田達士、山崎健太、忠垣憲次郎、桒原康道、酒井敏行、奥田司
  • Organizer: 第21回造血器腫瘍研究会
  • Place of Presentation: 熊本大学（熊本市）
  • Year and Date: 2017-02-17
• [Presentation] RUNX1/AML1転写因子の新規候補標的遺伝子の解析 (2017)
  • Author(s): 忠垣憲次郎、山崎健太、桒原康道、吉田達士、奥田司
  • Organizer: 第６４回日本生化学会近畿支部例会
• [Presentation] An array-based approach for novel RUNX1(AML1)-target genes. (2017)
  • Author(s): Kenjiro Tadagaki, Yasumichi Kuwahara, Tatsushi Yoshida, Tsukasa Okuda.
  • Organizer: 第７６回日本癌学会
• [Presentation] Candidate target genes of hematopoietic transcription factor RUNX1 (AML1). (2017)
  • Author(s): Kenjiro Tadagaki, Kenta Yamasaki, Yasumichi Kuwahara, Tatsushi Yoshida, Tsukasa Okuda.
  • Organizer: 第７９回日本血液学会
• [Presentation] 白血病由来RUNX1遺伝子変異体における機能的異常の解析 (2017)
  • Author(s): 吉田達士、山崎健太、忠垣憲次郎、桒原康道、近藤則子、奥田司
  • Organizer: 平成２９年度第７回４大学連携研究フォーラム
• [Presentation] Mechanism of recruitment of SWI/SNF complex via interaction between SNF5 and transcription factor. (2017)
  • Author(s): Yasumichi Kuwahara, Kenta Yamasaki, Kenjiro Tadagaki, Tatsushi Yoshida, Tsukasa Okuda.
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 白血病関連転写因子の制御法の開発と白血病治療に向けた応用 (2016)
  • Author(s): 吉田達士、山崎健太、忠垣憲次郎、桒原康道、奥田司
  • Organizer: 平成28年度第6回4大学連携研究フォーラム
  • Place of Presentation: 京都薬科大学（京都市）
  • Year and Date: 2016-12-07
• [Presentation] RUNX1/AML1はTRAILの転写制御に関与する (2016)
  • Author(s): 吉田達士、山崎健太、忠垣憲次郎、桒原康通、酒井敏行、奥田司
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-12-02
• [Presentation] A candidate target gene of RUNX1/AML1 transcription factor. (2016)
  • Author(s): Tatsushi Yoshida, Kenjiro Tadagaki, Kenta Yamasaki, Yasumichi Kuwahara, Toshiyuki Sakai, Tsukasa Okuda.
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-14
• [Presentation] A natural inhibitor of Runt-related Transcription Factor 1 / Acute Myeloid Leukemia 1 (RUNX1/AML1). (2016)
  • Author(s): Tatsushi Yoshida, Kenta Yamasaki, Kenjiro Tadagaki, Yasumichi Kuwahara, Tsukasa Okuda.
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 東北大学（仙台市）
  • Year and Date: 2016-09-26