Genetic and Epigenetic Regulation of Hematopoiesis.

描述（由申请人提供）：造血，即血细胞的产生，是一种至关重要的发育现象，为许多生物体提供氧气供应、免疫监视和激素循环。因此，该系统的正常发育和功能对于包括人类在内的许多动物物种的生存能力和健康至关重要;即使是该过程的轻微中断也可能导致衰弱和危及生命的病症，如贫血、血细胞减少、血友病、白血病和淋巴瘤。然而，尽管多年来在破译这一系统在各种生物体中的运作方面取得了重大进展，但它的许多方面仍然是一个谜。该提案的总体目标是在分子、细胞和整个生物体水平上建立哺乳动物从胚胎到成体的造血的基本原则和事件。Gfi-1（growth factor independence-1）和Gfi-1b是在哺乳动物造血中起重要和决定性作用的转录因子。Gfi-1是维持骨髓中成体干细胞功能完整性、中性粒细胞生成和适当淋巴发育所必需的。Gfi-1b对于红系细胞和巨核细胞谱系的产生以及原始（卵黄囊衍生的）红系细胞的适当分化是必需的。与这些基因在正常造血中的决定性作用一致，当它们在白血病和淋巴瘤中异位表达时，它们表现出恶性性质。鉴于我们最近的研究结果将Gfi-1和Gfi-1b与染色质修饰剂LSD 1（赖氨酸特异性脱甲基酶1），CoREST/Rcor 1（REST共阻遏物），其他Rcor同系物和组蛋白脱乙酰酶HDAC 1 -2联系起来，我们建议探索这些辅因子在与Gfi-1/1b一起建立转录和表观遗传程序中的作用。我们将进一步确定这些蛋白质的个体和组合作用如何影响血细胞从早期个体发育到成年阶段的形成，命运和功能。此外，我们将研究这些蛋白质及其辅因子在多种细胞环境中选择和调节Gfi-1/1b基因靶点的机制，并确定这些过程的生物学后果。这些实验将为哺乳动物造血发育的基本遗传和表观遗传编程提供有价值的见解和信息。这些见解将进一步作为理解LSD 1和Rcor蛋白产生类似作用的其他发育系统的范例。此外，通过研究这些因子的正常功能所获得的见解将阐明我们对正常条件下和血液病中干细胞和祖细胞生物学的整体观点。 公共卫生相关性：正常的造血，即血细胞的产生，对我们的生存和健康至关重要;这一过程的相对轻微的破坏可能导致衰弱和危及生命的疾病，如贫血，血细胞减少症，血友病，白血病和淋巴瘤。Gfi-1和Gfi-1b蛋白都是正常造血的重要调节因子，也表现出致癌倾向。阐明这些蛋白质及其在血细胞产生中的合作者的正常功能也将揭示这些基因的潜在恶性特性。

DESCRIPTION (provided by applicant): Hematopoiesis, the generation of blood cells, is a vital and essential developmental phenomenon providing oxygen supply, immune surveillance and hormone circulation to many organisms. Consequently, the normal development and functioning of this system is critical for the viability and well being of many animal species, including humans; even minor disruptions of this process can result in debilitating and life threatening conditions such as anemias, cytopenias, hemophilias, leukemias and lymphomas. Yet, despite major advances over the years in deciphering the workings of this system in a wide range of organisms, many aspects of it still remain a mystery. The overall goal of this proposal is to establish the fundamental principles and events of hematopoiesis from the embryo to the adult at the molecular, cellular and whole organism level in mammals. Gfi-1 (growth factor independence-1) and Gfi-1b are transcription factors that play essential and decisive roles in mammalian hematopoiesis. Gfi-1 is required for maintaining functional integrity of adult stem cells in the bone marrow, the generation of neutrophils and appropriate lymphoid development. Gfi-1b is essential for the generation of the erythroid and megakaryocytic lineages and for proper differentiation of primitive (yolk sac derived) erythroid cells. Consistent with the decisive roles of these genes in normal hematopoiesis, they exhibit malignant properties when ectopically expressed in leukemias and lymphomas. In light of our recent findings linking Gfi-1 and Gfi-1b to chromatin modifiers LSD1 (lysine specific demethylase1), CoREST/Rcor1 (REST co-repressor), other Rcor homologs and the histone deacetylases HDAC1-2, we propose to explore the role of these co-factors in establishing transcriptional and epigenetic programs in conjunction with Gfi-1/1b. We will further determine how the individual and combinatorial actions of these proteins impact the formation, fate and function of blood cells from early ontogeny to the adult stage. Additionally, we will investigate the mechanism of selection and regulation of Gfi-1/1b gene targets by these proteins and their cofactors in multiple cellular contexts and determine the biological consequences of these processes. These experiments will produce valuable insights and information into the fundamental genetic and epigenetic programming of hematopoietic development in mammals. These insights will further serve as paradigms for understanding other developmental systems where LSD1 and Rcor proteins produce similar effects. Moreover, insights gained by studies into the normal function of these factors will illuminate our overall perspective of stem and progenitor cell biology, both under normal conditions and in hematological diseases. PUBLIC HEALTH RELEVANCE: Normal hematopoiesis, the generation of blood cells, is vital to our survival and wellbeing; relatively minor disruptions of this process can result in debilitating and life threatening conditions such as anemias, cytopenias, hemophilias, leukemias and lymphomas. Gfi-1 and Gfi-1b proteins are both essential regulators of normal hematopoiesis and also exhibit oncogenic propensities. Elucidating the normal functions of these proteins and their collaborators in blood cell production will also uncover the latent malignant properties of these genes.