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; 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. !

项目摘要 血小板对于止血，血栓形成和炎症反应至关重要。数十亿个血小板流通 哺乳动物血液以防止组织损伤的血液损失。血小板的寿命很短（5-9天 人类）；结果，必须每小时生产几百万个血小板才能维护其 生理血液计数并避免出血的风险。血小板是从骨髓中产生的 巨核细胞反过来又是由造血茎和祖细胞（HSPC）发展而来的。虽然 重要的信号通路和转录因子已显示在血小板中起重要作用 生物发生（血小板），对此过程的表观遗传调节知之甚少 涉及的表观遗传调节剂。因为表观遗传调节器是调节网络的重要组成部分 该在细胞分化过程中与转录因子合作，缺乏此类知识 显着阻碍了控制血小板产生和功能的分子网络的阐明。我们 已经在MLL3/4（混合谱系白血病3＆4; KMT2C/KMT2D）组中发表了重要工作 甲基转移酶（KMT）复合物，包括发现MLL4在髓样白血病中的重要作用 对于MLL3/4复合物适配器亚基PTIP（与转录激活域蛋白-1的PAX相互作用） 淋巴细胞类转换重组，最近在维持正常和白血病造血茎中 细胞生态位。对于后者的研究，我们已经生成了PTIP中有条件失活的小鼠模型 HSPC并始终观察到PTIP缺乏导致血小板减少症。我们最近产生了MK- 特定的小鼠模型，并确定观察到的血小板减少是PTIP的内在作用 在MK谱系中删除。对MLL4缺陷型小鼠进行的初步分析显示，很温和，但 显着的，血小板减少症。根据我们的初步数据和已发布的工作，我们假设PTIP是 通过与MLL3和MLL4一起运行血小板所需的血小板特异性 基因表达程序。该项目的目的是确定PTIP及其相关的作用 血小板生成的KMTS MLL3/4。预计拟议研究的结果将从根本上 通过进一步定义调节血小板的表观遗传机制，推进血小板生物学领域 一代。最后，我们工作的结果可能有助于开发新型体​​内疗法 旨在增强血小板的血小板产生或血小板的体内扩张。我们的长期目标是利用 组蛋白翻译后修饰以促进人类健康的可逆性。 呢