Epigenetic changes in hematopoietic system during aging and molecular basis of hematopoietic tumor

• Project/Area Number: 18K08348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Oshima Motohiko 東京大学, 医科学研究所, 助教 (70506287)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 加齢 / 造血 / 造血幹細胞 / ATAC-seq / 加齢変化 / RNA-seq / Ezh2リン酸化 / Nrf2

Outline of Final Research Achievements

To explore the difference in hematopoietic system during aging and clarify the pathogenic
significance in hematopoietic disease, we perform RNA-seq and ATAC-seq using hematopoietic stem and progenitor cells to evaluate the differentially expressed genes and differentially accessible regions respectively. The results showed that many transcription factor networks has been changed during aging, indicating that the history of exposure to external stresses are epigenetically inscribed in HSCs to augment their responses to subsequent stimuli.

Academic Significance and Societal Importance of the Research Achievements

本研究では、若齢および老齢マウスの造血幹、前駆細胞の変化について検証を行った結果、加齢に伴い外的ストレスに関わる様々な転写因子ネットワークが変化することが明らかになった。本研究により解明された、加齢に伴う造血システムの生理的な変化の分子基盤を通じて、高齢化社会において急増しつつある、加齢関連造血器疾患の発症予防や新規治療法の開発に繋がることが期待される。

Research Products

• [Journal Article] Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche (2021)
  • Author(s): Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki S, Rahmutulla B, Miura F, Ito T, Kaneda A, Iwama A.
  • Journal Title: J Exp Med Volume: 218 Issue: 3
  • DOI: 10.1084/jem.20192283
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature. (2020)
  • Author(s): Nitta E, Itokawa N, Yabata S, Koide S, Hou LB, Oshima M, Aoyama K, Saraya A, Iwama A.
  • Journal Title: Biochem Biophys Res Commun Volume: 521 Issue: 3 Pages: 612-619
  • DOI: 10.1016/j.bbrc.2019.10.153
  • Peer Reviewed / Open Access
• [Journal Article] Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma. (2019)
  • Author(s): Rizk M, Rizq O, Oshima M, Nakajima-Takagi Y, Koide S, Saraya A, Isshiki Y, Chiba T, Yamazaki S, Ma A, Jin J, Iwama A, Mimura N.
  • Journal Title: Cancer Sci Volume: 110 Issue: 12 Pages: 3695-3707
  • DOI: 10.1111/cas.14207
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis. (2019)
  • Author(s): Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Rizk M, Kurosawa S, Saraya A, Kondo T, Sakaida E, Nakaseko C, Yokote K, Koseki H, Iwama A.
  • Journal Title: Blood Adv Volume: 3 Issue: 17 Pages: 2537-2549
  • DOI: 10.1182/bloodadvances.2018028522
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The chromatin binding protein Phf6 restricts the self-renewal of hematopoietic stem cells. (2019)
  • Author(s): Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, Takayama N, Saraya A, Mizuno S, Sugiyama F, Takahashi S, Matsuzaki Y, Christensen J, Helin K, and Iwama A.
  • Journal Title: Blood Volume: - Issue: 23 Pages: 2495-2506
  • DOI: 10.1182/blood.2019000468
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deregulated Polycomb functions in myeloproliferative neoplasms. (2019)
  • Author(s): Sashida G, Oshima M, Iwama A.
  • Journal Title: Int J Hematol Volume: 110 Issue: 2 Pages: 170-178
  • DOI: 10.1007/s12185-019-02600-6
  • Peer Reviewed / Open Access
• [Journal Article] Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome. (2018)
  • Author(s): Aoyama K, Oshima M, Koide S, Suzuki E, Mochizuki-Kashio M, Kato Y, Tara S, Shinoda D, Hiura N, Nakajima-Takagi Y, Sashida G, Iwama A.
  • Journal Title: iScience Volume: 9 Pages: 161-174
  • DOI: 10.1016/j.isci.2018.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome. (2018)
  • Author(s): Tara S, Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Tanaka T, Shinoda D, Koide S, Saraya A, Miyagi S, Manabe I, Matsui H, Koseki H, Bardwell VJ, Iwama A.
  • Journal Title: Blood Volume: 132(23) Issue: 23 Pages: 2470-2483
  • DOI: 10.1182/blood-2018-01-827964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ezh2 loss propagates hypermethylation at T cell differentiation?regulating genes to promote leukemic transformation (2018)
  • Author(s): Wang Changshan、Oshima Motohiko、Sato Daisuke、Matsui Hirotaka、Kubota Sho、Aoyama Kazumasa、Nakajima-Takagi Yaeko、Koide Shuhei、Matsubayashi Jun、Mochizuki-Kashio Makiko、Nakano-Yokomizo Takako、Bai Jie、Nagao Toshitaka、Kanai Akinori、Iwama Atsushi、Sashida Goro
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 9 Pages: 3872-3886
  • DOI: 10.1172/jci94645
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells. (2018)
  • Author(s): Si S, Nakajima-Takagi Y, Iga T, Tsuji M, Hou L, Oshima M, Koide S, Saraya A, Yamazaki S, Takubo K, Kubota Y, Minamino T, Iwama A.
  • Journal Title: Exp Hematol Volume: 63 Pages: 41-51
  • DOI: 10.1016/j.exphem.2018.04.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Profiling of chromatin accessibility of aged hematopoietic stem cells (2020)
  • Author(s): Oshima M, Takayama N, Nakajima-Takagi Y, Koide S, Aoyama K, Iwama A.
  • Organizer: 第15回生命医科学研究所ネットワーク国際シンポジウム
  • Int'l Joint Research
• [Presentation] Epigenetic changes in hematopoietic stem and progenitor cells during aging (2020)
  • Author(s): Oshima M, Nakajima-Takagi Y, Koide S, Aoyama K, Takayama N, Iwama A.
  • Organizer: 第82回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] Activation of Keap1-Nrf2 pathway in HSCs during aging. (2019)
  • Author(s): Oshima M, Aoyama K, Nakajima-Takagi Y, Koide S, Iwama A.
  • Organizer: 第17回幹細胞シンポジウム
• [Presentation] Epigenetic hallmarks of aging hematopoietic stem cells. (2018)
  • Author(s): Oshima M, Itokawa N, Kuribayashi W, Aoyama K, Nakajima-Takagi Y, Koide S, Iwama A.
  • Organizer: 第16回幹細胞シンポジウム
• [Presentation] Activation of Keap1-Nrf2 pathway in HSCs during aging. (2018)
  • Author(s): Oshima M, Aoyama K, Nakajima-Takagi Y, Koide S, Iwama A.
  • Organizer: 第80回日本血液学会学術集会