Dynamic regulation of the epigenome during hematopoietic differntiation

描述(由申请人提供)： 自我更新对于许多器官系统的动态平衡和终生维持是必不可少的。自我更新的过程是由稀有的成体干细胞群体进行的，其关键特征是多谱系潜力和再繁殖能力。血细胞的发育是由细胞命运的连续限制推动的，因为多能造血干细胞(HSCs)产生了所有成熟的红细胞和白细胞类型。目前的模型表明，DNA甲基化的细胞类型特定模式的积累与细胞命运规范相关，标记模式既创建了细胞谱系的记录，又由于此类标记的先天遗传性而将该细胞锁定在特定的命运中。我们建议制作人类和小鼠在HSC分化过程中DNA甲基化的全基因组参考图谱。我们的研究将比较长期重新繁殖的HSCs纯化群体中小鼠和人类的甲基组状态。我们将评估表型决定命运的最早的祖细胞中特定谱系的标记模式，并跟踪随后通过血细胞成熟的表观基因组的重塑。这项研究将通过一个具有良好特征的发育级联来提供第一次对表观基因组状态的全面检查。通过两个不同模型的比较研究，我们希望将驱动命运指定和限制决定的关键事件与那些可能简单地 与细胞分化有关。 公共卫生相关性： 将长期的造血干细胞分化为成熟的红细胞和白细胞是动物发育过程中研究最多的过程之一。随着更多的原始细胞转变为更分化和专门化的细胞类型，伴随着基因组表观遗传状态的变化被认为加强了这些决定。我们建议在人类和小鼠的造血系统中检测干细胞和成熟细胞中表观基因组的状态。通过这种方式，我们将揭示决定细胞命运的一般原理，并了解细胞如何变得越来越限制其潜力。这些研究还可能揭示为治疗目的创造特定类型的造血细胞的策略。

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.