Role of H3K36 methyltransferase Mmset in Hematopoietic stem cells

• Project/Area Number: 16K19566
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: Mochizuki Makiko 千葉大学, 大学院医学研究院, 特任研究員 (40751300)
• Research Collaborator: IWAMA Atsushi ; URA Kiyoe
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Mmset / Whsc1 / Nsd1 / HSC / H3K36me2/3 / Nsd2 / FA / MMSET / ヒストン修飾 / 造血幹細胞 / 分化 / DNAダメージ修復

Outline of Final Research Achievements

Wolf-Hirschhorn syndrome candidate 1 (WHSC1), also known as NSD2 or MMSET, functions as a one of the Histone H3 Lysin36 methyltransferase (H3K36me) transcriptional regulation together with developmental transcription factors and that the Whsc1 deficiency is responsible for WHS.
In this reserch, we showed that Whsc1 is required for normal Hematopoietic stem cell (HSC) homeostasis. We performed Hematopoietic analysis in both Whsc1 conventional knockout (KO) and conditional knockout (cKO) mice. HSC number was slightly increased in adult Whsc1 cKO. Nevertheless competitive reconstitution of hematopoietic cell analysis reveals that Whsc1-deficient HSCs impaired reconstitution capacity in vivo. These data indicate DNA damage repair associated modification H3K36me plays important role for HSC self-renewal, differentiation and reconstitution.

Research Products

• [Journal Article] The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang C, Tomioka T, Oshima M, Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, and Iwama A.
  • Journal Title: J Exp Med Volume: 25;213(8) Pages: 1459-1477
  • Peer Reviewed
• [Journal Article] Ezh2 regulates the Lin28/let-7 pathway to re- strict 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, Wendt GR, Saraya A, Wang C, Shimoda K, Suzuki Y, Iwama A.
  • Journal Title: Exp Hematol. Volume: 44(4) Pages: 282-296
  • Peer Reviewed
• [Presentation] メチル化転移酵素Nsd2の機能の解明 (2017)
  • Author(s): 望月（樫尾）牧子、横田貴文、藤木亮次、杉尾ジュリー、鈴木慈、 前田亮、岩間厚志、浦聖恵
  • Organizer: 染色体ワークショップ
  • Place of Presentation: かずさアカデミアホール202B会議場（千葉県・木更津市）
  • Year and Date: 2017-01-11
• [Presentation] ヒストンH3K36転移酵素Whsc1の造血幹細胞における機能の解明 (2016)
  • Author(s): 望月（樫尾）牧子、岩間厚志、浦聖恵
  • Organizer: 転写サイクル班会議2016
  • Place of Presentation: 松島一の坊（宮城県・松島町）
  • Year and Date: 2016-09-05
• [Presentation] Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Eh1-dependent manner (2016)
  • Author(s): Makiko Mochizuki-Kashio, Kazumasa Aoyama, Goro Sashida, Motohiko Oshima, Changshan Wang, Atushi Iwama
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: Tokyo Bay Maihama Hotel Club Resort（千葉県・浦安市）
  • Year and Date: 2016-07-13
• [Presentation] Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Eh1-dependent manner (2016)
  • Author(s): Makiko Mochizuki-Kashio, Kazumasa Aoyama, Goro Sashida, Motohiko Oshima, Changshan Wang, Atushi Iwama
  • Organizer: 幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県・淡路市）
  • Year and Date: 2016-05-21
• [Presentation] Ezh2の機能欠損による造血器腫瘍の形成には造血幹・前駆細胞におけるEzh1の発現が必須である (2016)
  • Author(s): 樫尾（望月） 牧子、青山 和正、指田 吾郎、大島 基彦、王 長山、 岩間 厚志
  • Organizer: 麒麟塾
  • Place of Presentation: コクヨホール（東京都・品川区）