Epigenetic bases for HSCs aging and development of hematopoietic disorder

• Project/Area Number: 16K20959
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology; Medical genome science
• Research Institution: Chiba University
• Principal Investigator: Oshima Motohiko 千葉大学, 大学院医学研究院, 助教 (70506287)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 老化造血幹細胞 / PRC2 / 老化 / H3K27me3 / 造血幹細胞 / ポリコーム / 血液内科学

Outline of Final Research Achievements

We found that PRC2 target genes were de-repressed in aged hematopoietic stem cells (HSCs) compared with young HSCs. We performed ChIP-seq and found that H3k27me3 levels of PRC2 target genes around TSS were significantly decreased in aged HSCs. chronic inflammation stress, which is known to be one of aging stress, caused significantly decreased H3K27me3 levels and acquired aging gene expression profile. In aged HSCs, we found that Ezh2 S21 phosphorylation, which is related to dysfunction of PRC2 complex, was significantly increased.

Research Products

• [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies (2017)
  • Author(s): Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2901-2913
  • DOI: 10.1084/jem.20170167
  • Peer Reviewed / Open Access
• [Journal Article] Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition. (2017)
  • Author(s): Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Tetsuhiro Chiba, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, and Atsushi Iwama
  • Journal Title: Clinical Cancer Research Volume: 23(16) Issue: 16 Pages: 4817-4830
  • DOI: 10.1158/1078-0432.ccr-16-2735
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. (2016)
  • Author(s): Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
  • Journal Title: Leukemia Volume: in press Issue: 4 Pages: 861-871
  • DOI: 10.1038/leu.2016.268
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang S, Tomioka T, Oshima M, Kazumasa Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A.
  • Journal Title: J Experimenta l Medicine Volume: 213 Issue: 8 Pages: 1459-1477
  • DOI: 10.1084/jem.20151121
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes. (2016)
  • Author(s): Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
  • Journal Title: Blood Volume: 128(5) Issue: 5 Pages: 638-649
  • DOI: 10.1182/blood-2016-01-694810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells (2016)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells. (2016)
  • Author(s): Oshima M, Hasegawa N, Mochizuki-Kashio M, Muto T, Miyagi S, Koide S, Yabata S, George Wendt GR, Saraya A, Wang C, Shimoda K, Suzuki Y, Iwama A. Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells.
  • Journal Title: Exp Hemato Volume: 44(4) Issue: 13 Pages: 282-296
  • DOI: 10.1182/blood-2015-08-661421
  • Peer Reviewed
• [Presentation] Functional defect of Polycomb group complex during hematopoietic cell aging and myelid malignancies (2017)
  • Author(s): Motohiko Oshima, Kazumasa Aoyama, Changshan Wang, Shuhei Koide, Atsushi Iwama
  • Organizer: NGS現場の会 第五回研究会
• [Presentation] Functional defect of Polycomb group complex during hematopoietic stem cell aging and myelid malignancies (2017)
  • Author(s): Motohiko Oshima, Kazumasa Aoyama, Changshan Wang, Shuhei Koide, Atsushi Iwama
  • Organizer: 第15回 幹細胞シンポジウム
• [Presentation] Profiling of transcriptional properties of aged hematopoietic stem and progenitor cells (2016)
  • Author(s): Motohiko Oshima, Changshan Wang, Shuhei Koide, Atsushi Iwama
  • Organizer: 第78回 日本血液学会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-13
  • Int'l Joint Research
• [Presentation] 造血幹細胞老化に関わるポリコーム群複合体機能異 常の解明 (2016)
  • Author(s): 大島基彦, 小出周平, 岩間厚志
  • Organizer: 第８９回日本生化学会
  • Place of Presentation: 仙台国際センター(宮城県、仙台市）
  • Year and Date: 2016-09-25
  • Int'l Joint Research