Epigenetic regulation of thrombopoiesis

血小板生成的表观遗传调控

• 批准号: 10320440
• 负责人: Taiping Chen
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320440
• 关键词: Adaptor Signaling Protein; Affect; Animals; Antibodies; Biogenesis; Biological Assay; Biology; Blood; Blood Cells; Blood Platelets; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Involvement; Cells; ChIP-seq; Chromatin; Complex; Data; Development; Disease; Electron Microscopy; Enhancers; Epigenetic Process; FLI1 gene; Flow Cytometry; Fluorescence Microscopy; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Goals; Health; Hematopoietic stem cells; Hemorrhage; Hemostatic function; Hour; Human; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; In Vitro; Inflammatory Response; Knowledge; Leukemic Hematopoietic Stem Cell; Longevity; Lymphocyte; Megakaryocytes; Megakaryocytopoieses; Mixed-Lineage Leukemia; Molecular; Mus; Myeloid Leukemia; Nucleic Acid Regulatory Sequences; PF4 Gene; Phase; Physiological; Platelet Count measurement; Play; Population; Post-Translational Protein Processing; Process; Production; Publishing; RNA immunoprecipitation sequencing; RUNX1 gene; Risk; Role; Signal Pathway; Tertiary Protein Structure; Testing; Thrombocytopenia; Thrombopoiesis; Thrombosis; Transcriptional Activation Domain; Transcriptional Regulation; Translations; Work; base; epigenetic regulation; histone methyltransferase; histone modification; in vivo; mouse model; novel; prevent; progenitor; programs; promoter; recruit; tissue injury; transcription factor; transcriptome sequencing

PROJECT SUMMARY Platelets are critical for hemostasis, thrombosis and inflammatory responses. Billions of platelets circulate in mammalian blood to prevent blood loss in case of tissue injury. The lifespan of platelets is short (5-9 days in humans); as a consequence, several million platelets have to be produced every hour to maintain their physiological blood counts and to avoid the risk of bleeding. Platelets are generated in the bone marrow from megakaryocytes that, in turn, develop from hematopoietic stem and progenitor cells (HSPCs). Although important signaling pathways and transcription factors have been shown to play important roles in platelet biogenesis (thrombopoiesis), little is known about the epigenetic regulation of this process and the key epigenetic regulators involved. Because epigenetic regulators are essential components of regulatory networks that act collaboratively with transcription factors during cellular differentiation, lack of such knowledge significantly hinders the elucidation of the molecular networks controlling platelet generation and function. We have published significant work on the MLL3/4 (mixed lineage leukemia 3&4; KMT2C/KMT2D) histone methyltransferase (KMT) complex, including uncovering an important role for MLL4 in myeloid leukemia, a role for the MLL3/4 complex adaptor subunit PTIP (Pax interaction with transcription-activation domain protein-1) in lymphocyte class switch recombination and, recently, in maintaining normal and leukemic hematopoietic stem cell niches. For the latter studies, we have generated a mouse model of conditional inactivation of PTIP in HSPCs and consistently observed that PTIP deficiency led to thrombocytopenia. We recently generated a MK- specific mouse model and established that the observed reduction in platelets is an intrinsic effect of PTIP deletion in the MK lineage. Preliminary analysis performed on MLL4-deficient mice revealed mild, but significant, thrombocytopenia. Based on our preliminary data and published work, we hypothesize that PTIP is required for platelet generation by functioning together with MLL3 and MLL4 to direct a thrombopoiesis-specific gene expression program. The objective of this project is to determine the role of PTIP and its associated KMTs MLL3/4 in platelet generation. Results from the proposed studies are expected to fundamentally advance the fields of platelet biology by further defining the epigenetic mechanisms that regulate platelet generation. Finally, results from our work will likely contribute to the development of novel in vivo therapies aimed at enhancing platelet production or ex vivo expansion of platelets. Our long-term goal is to harness the reversibility of post-translation modifications of histones to promote human health. !

项目概要 血小板对于止血、血栓形成和炎症反应至关重要。数十亿血小板在体内循环 哺乳动物的血液，以防止组织损伤时失血。血小板的寿命很短（5-9天） 人类）；因此，每小时必须产生数百万个血小板才能维持其功能 生理血细胞计数并避免出血风险。血小板是在骨髓中产生的 巨核细胞又由造血干细胞和祖细胞 (HSPC) 发育而来。虽然 重要的信号通路和转录因子已被证明在血小板中发挥重要作用 生物发生（血栓形成），但对该过程的表观遗传调控及其关键知之甚少 涉及表观遗传调节因子。因为表观遗传调控因子是调控网络的重要组成部分 在细胞分化过程中与转录因子协同作用，缺乏这方面的知识 显着阻碍了控制血小板生成和功能的分子网络的阐明。我们 发表了有关 MLL3/4（混合谱系白血病 3&4；KMT2C/KMT2D）组蛋白的重要工作 甲基转移酶 (KMT) 复合物，包括揭示 MLL4 在髓系白血病中的重要作用， MLL3/4 复合体衔接子亚基 PTIP（Pax 与转录激活域蛋白-1 的相互作用） 淋巴细胞类别转换重组，以及最近在维持正常和白血病造血干中的作用 细胞壁龛。对于后面的研究，我们建立了 PTIP 条件失活的小鼠模型 HSPC 并一致观察到 PTIP 缺乏会导致血小板减少症。我们最近生成了一个 MK- 特定小鼠模型，并确定观察到的血小板减少是 PTIP 的内在作用 MK谱系中的缺失。对 MLL4 缺陷小鼠进行的初步分析显示，症状轻微，但 显着，血小板减少。根据我们的初步数据和已发表的工作，我们假设 PTIP 是 血小板生成所需的，通过与 MLL3 和 MLL4 一起发挥作用来指导血小板生成特异性 基因表达程序。该项目的目标是确定 PTIP 及其相关机构的作用 KMTs MLL3/4 在血小板生成中的作用。拟议研究的结果预计将从根本上 通过进一步定义调节血小板的表观遗传机制来推进血小板生物学领域 一代。最后，我们的工作结果可能有助于新型体内疗法的开发 旨在增强血小板产生或血小板的离体扩增。我们的长期目标是利用 组蛋白翻译后修饰的可逆性以促进人类健康。 ！