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Poster Networking

Platelets and Megakaryocytes

PB0724 - SETD2 Promotes Megakaryocyte Polyploidization and Platelet Generation through Methylation of α-tubulin

Monday, June 24, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Presenting Author(s)

  • Jingkun Liu

    PhD student
    Beijing Institute of Genomics, Chinese Academy of Sciences (CAS)
    Beijing, Beijing, China (People's Republic)

    • Co-Author(s)

  • CL

    Chen Lei

    Research Assistant
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • KC

    Kunying Chen

    PhD student
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • YS

    Yanxun Su

    PhD student
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • YC

    Yihe Chen

    MD Student
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • YL

    Ying Lei

    Post-doctor
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • JS

    Jia Si

    PhD student
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • JZ

    Jie Zhang

    PhD student
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • ZZ

    Zhaojun Zhang

    Associate professor
    Beijing Institute of Genomics
    Beijing, Beijing, China (People's Republic)

  • WZ

    Weiguo Zou

    Professor
    CAS Center for Excellence in Molecular Cell Science
    Shanghai, Shanghai, China (People's Republic)

  • XZ

    Xiaohui Zhang

    Professor
    Peking University People’s Hospital
    Beijing, Beijing, China (People's Republic)

  • Matthew T. Rondina, MD

    Professor
    Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; 4George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research, Education, and Clinical Center; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
    Salt Lake City, Utah, United States

  • QW

    Qian-fei Wang

    Principle Investigator
    Beijing Institute of Genomics, Chinese Academy of Sciences (CAS)
    Beijing, Beijing, China (People's Republic)

  • Yueying Li, MD

    Professor
    Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation
    Beijing, Beijing, China (People's Republic)

Background: Megakaryocytes (MKs) are polyploid cells responsible for producing ~10*11 platelets daily in humans. Unraveling the mechanisms regulating megakaryopoiesis holds the promise for the production of clinical-grade platelets from stem cells, overcoming significant current limitations in platelet transfusion medicine. Previous work identified that loss of the epigenetic regulator SETD2 was associated with an increased platelet count in mice. However, the role of SETD2 in megakaryopoiesis remains unknown.

Aims: To investigate how SETD2 regulated MK development and platelet production using complementary murine and human systems.

Methods: Ploidy analysis of megakaryocytes (MKs) and functional platelet assays, including counting, aggregation, adhesion, cytokine production, and spreading, were conducted in the Setd2 knockout mouse model. In in vitro cultures of MKs derived from human CD34+ cells or induced pluripotent stem cells (iPSCs), SETD2 expression was manipulated through knockdown, overexpression, or inhibition using small molecules.

Results: The genetic ablation of Setd2 increased the number of high-ploidy bone marrow MKs. Peripheral platelet counts in Setd2 knock-out mice were significantly increased ~2-fold and platelets exhibited normal size, morphology, and function. By knocking down and overexpressing SETD2 in ex vivo human cell systems, we demonstrated that SETD2 negatively regulated MK polyploidization by controlling methylation of α-tubulin, microtubule polymerization, and MK nuclear division. Small molecule inactivation of SETD2 significantly increased the production of high ploidy MKs and platelets from human induced pluripotent stem cells and cord-blood CD34+ cells.

Conclusion(s): These findings identify a previously unrecognized role for SETD2 in regulating megakaryopoiesis and highlight the potential of targeting SETD2 to increase platelet production from human cells for transfusion practices.