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: 7942835
• 负责人: THOMAS Raymond GINGERAS
• 金额: $ 110.33万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942835
• 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生维护至关重要。自我更新的过程是由罕见的成年干细胞种群进行的，其主要特征是多节势的潜力和重新流动能力。由于多能造血干细胞（HSC）的连续限制，血细胞的发育驱动了，这会导致所有成熟的红色和白细胞类型。当前的模型表明，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，标记的模式既创造了细胞的谱系记录，又将该细胞锁定在特定的命运中，这是由于这种标记的先天性遗传力。我们建议在HSC分化过程中生成整个人和小鼠基因组中DNA甲基化的全基因组参考图。我们的研究将比较在长期重新流传HSC的纯化种群中的鼠和人甲基组的状态。我们将评估表型指定命运的最早的祖细胞中的谱系特异性模式，并通过血细胞成熟来遵循表观基因组的重塑。这项研究将通过表征良好的发育级联对表观基因组的状态进行首次全面检查。尽管在两个不同的模型中进行了比较研究，但我们希望将推动命运规范和限制决策的关键事件与可能只是简单的限制决策分开 与细胞分化相关。 公共卫生相关性： 长期造血干细胞为成熟的红色和白细胞的分化是动物研究最佳的发育过程之一。随着更原始的细胞变成更具分化和专业的细胞类型，伴随基因组表观遗传状态的变化被认为可以加强这些决定。我们建议检查人类和小鼠造血系统中干细胞和成熟细胞中表观遗传组的状态。通过这种方式，我们将揭示细胞命运确定的一般原则，并了解细胞如何越来越限制其潜力。这些研究还可能揭示了为治疗目的创建特定类型的造血细胞的策略。