Dynamic regulation of the epigenome during hematopoietic differntiation

造血分化过程中表观基因组的动态调控

• 批准号: 7859767
• 负责人: THOMAS Raymond GINGERAS
• 金额: $ 140.19万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859767
• 关键词: Adopted; Animals; Biological; Blood Cells; Bone Marrow; Cell Differentiation process; Cell Lineage; Cell Maturation; Cells; Comparative Study; DNA Methylation; DNA Modification Process; Development; Developmental Process; Epigenetic Process; Event; Functional RNA; Gene Expression; Genetic Transcription; Genome; Goals; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Heritability; Homeostasis; Human; In Vitro; Leukocytes; Lymphocyte; Lymphoid; Maintenance; Maps; Mature T-Lymphocyte; Methods; Methylation; MicroRNAs; Modeling; Modification; Molecular Profiling; Mus; Myelogenous; Pattern; Peripheral; Play; Population; Process; Reading; Regulation; Reporting; Research Design; Resolution; Role; Sampling; Shotguns; Signal Transduction; Small RNA; Specific qualifier value; Staging; Stem cells; Therapeutic; Transcript; Umbilical Cord Blood; Validation; adult stem cell; base; bisulfite; body system; cell fate specification; cell type; cost; genome-wide; macrophage; mouse genome; primitive cell; progenitor; programs; public health relevance; self-renewal; stem cell differentiation

DESCRIPTION (provided by applicant): Self-renewal is essential for the homeostasis and lifetime maintenance of many organ systems. The process of self-renewal is carried out by rare populations of adult stem cells whose key features are multilineage potential and repopulating capacity. Blood cell development is driven by the successive restriction of cell fate as multipotent hematopoietic stem cells (HSCs) give rise to all mature red and white blood cell types. Current models suggest that the accumulation of cell-type specific patterns of DNA methylation correlates with cell fate specification, with the pattern of marks both creating a record of a cell's lineage and locking that cell into a particular fate due to the innate heritability of such marks. We propose to produce genome-wide reference maps of DNA methylation throughout the human and mouse genomes during HSC differentiation. Our studies will compare the state of the murine and human methylomes in purified populations of long-term repopulating HSCs. We will assess lineage-specific patterns of marks in the earliest progenitor cells for which fate is phenotypically specified, and follow the subsequent remodeling of the epigenome through blood cell maturation. This study will provide the first comprehensive examination of the state of the epigenome through a well characterized developmental cascade. Though comparative studies in two distinct models, we hope to separate the key events that drive fate specification and restriction decisions from those that might simply correlate with cell differentiation. PUBLIC HEALTH RELEVANCE: The differentiation of long-term hematopoietic stem cells into mature red and white blood cells is one of the best studied developmental processes in animals. As more primitive cells turn into more differentiated and specialized cell types, accompanying changes in the epigenetic state of the genome are thought to reinforce these decisions. We propose to examine the state of the epigenome in both stem cells and mature cells within the hematopoietic system in humans and mice. In this way, we will reveal general principles of cell fate determination and understand how cells become increasingly restricted in their potential. These studies may also reveal strategies to create specific types of hematopoietic cells for therapeutic purposes.

描述（由申请人提供）： 自我更新对于许多器官系统的稳态和终身维持是必不可少的。自我更新的过程是由罕见的成体干细胞群体进行的，其关键特征是多谱系潜力和再生能力。血细胞发育受细胞命运的连续限制驱动，因为多能造血干细胞（HSC）产生所有成熟的红细胞和白色血细胞类型。目前的模型表明，DNA甲基化的细胞类型特异性模式的积累与细胞命运规范相关，标记的模式既创建了细胞谱系的记录，又由于这些标记的先天遗传性而将该细胞锁定在特定的命运中。我们建议在整个人类和小鼠基因组中产生HSC分化过程中DNA甲基化的全基因组参考图谱。我们的研究将比较鼠和人甲基化组在纯化的长期再生HSC群体中的状态。我们将评估最早的祖细胞中的标志物的谱系特异性模式，并通过血细胞成熟来跟踪表观基因组的后续重塑。这项研究将提供第一个全面的检查状态的表观基因组通过一个良好的特点发展级联。通过在两个不同模型中的比较研究，我们希望将驱动命运规范和限制决策的关键事件与那些可能简单地 与细胞分化有关。 公共卫生关系： 长期造血干细胞分化为成熟的红细胞和白色血细胞是动物中研究最多的发育过程之一。随着更原始的细胞变成更分化和特化的细胞类型，基因组表观遗传状态的伴随变化被认为会加强这些决定。我们建议检查人类和小鼠造血系统中干细胞和成熟细胞的表观基因组状态。通过这种方式，我们将揭示细胞命运决定的一般原则，并了解细胞如何在其潜力中变得越来越受限制。这些研究还可能揭示为治疗目的创造特定类型造血细胞的策略。