Epigenetic Regulation of Hematopoietic Stem Cell Specification

描述(由申请人提供)：造血干细胞的表观遗传学调节规范概述白血病是一种细胞功能紊乱、基因表达异常和持续存活的多方面疾病。白血病细胞的一些特征使人联想到干细胞的功能，例如自我更新的能力。癌细胞如何获得或重新获得这些特征尚不清楚，尽管易位产物中染色质重塑因子的存在提示了染色质重塑的作用。同样，关于造血干细胞(HSC)发育过程中染色质的重塑仍有许多未知之处。在这里，我们建议以斑马鱼为模型系统，揭示调节HSC规格的染色质重塑因子。为此，我们将阐明染色质重构体Polycomb家族在造血中的作用，并建立与Wnt和Notch通路相关的Polycomb活性的层次结构，这两个通路在造血规范和维持中都是必不可少的。我们还将使用基于吗啡的基因表达敲除方法进行反向遗传筛查，以揭示建立HSC和HSC表观遗传密码所必需的因素。由于许多与白血病相关的途径和调节因子也控制着造血，因此，明确HSC指定和维持的基本机制将阐明肿瘤病变所利用的正常细胞功能中的关键因素，从而成为治疗方法的靶点。 公共卫生相关性：这项提案中概述的研究将确定改变造血干细胞发育的因素，当调控不当时，可能会导致白血病表型。我们的工作旨在识别新的白血病标志物，并更准确地确定白血病患者的诊断和预后。此外，对特定基因缺陷的了解可能有助于选择特定的疗程，并可能对开发新的治疗方法有用。

DESCRIPTION (provided by applicant): Epigenetic Regulation of Hematopoietic Stem Cell Specification SUMMARY Leukemia is a multifaceted disease of disrupted cell function, aberrant gene expression and sustained survival. Some characteristics of leukemia cells are reminiscent of stem cell functions, such as the ability for self-renewal. How cancer cells obtain or re-acquire these characteristics remains unknown, though a role for chromatin remodeling is suggested by the presence of chromatin remodeling factors in translocation products. Similarly, much remains unknown regarding chromatin remodeling in hematopoietic stem cell (HSC) development. Here, we propose to uncover chromatin remodeling factors that regulate HSC specification using zebrafish as a model system. To this end, we will elucidate the role of the Polycomb family of chromatin remodelers in hematopoiesis and establish a hierarchy for Polycomb activity in relation to the Wnt and Notch pathways, both essential in hematopoietic specification and maintenance. We will also conduct a reverse genetic screen using a morpholino-based gene expression knockdown approach to reveal factors necessary for the establishment of HSCs and the HSC epigenetic code. As many of the pathways and regulators associated with leukemia also control hematopoiesis, defining the basic mechanisms of HSC specification and maintenance will illuminate critical factors in normal cell function that cancerous lesions exploit and thus be targeted in therapeutic approaches. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal will identify factors that alter hematopoietic stem cell development and, when misregulated, may contribute to a leukemic phenotype. Our work aims to identify novel leukemic markers and more accurately determine a diagnosis and prognosis for leukemia patients. Furthermore, knowledge of specific genetic defects may help in selecting a particular course of treatment and may be useful in developing new therapies.