Genetic and Epigenetic Regulation of Hematopoiesis.

描述(申请人提供)：造血，血细胞的产生，是一种重要和必要的发育现象，为许多生物体提供氧气供应、免疫监测和激素循环。因此，这一系统的正常发展和功能对包括人类在内的许多动物物种的生存和福祉至关重要；即使这一过程的轻微中断也可能导致贫血、细胞减少症、血友病、白血病和淋巴瘤等虚弱和危及生命的情况。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。这项提议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基本造血原理和事件。GFI-1(生长因子独立性-1)和GFI-1b是在哺乳动物造血中起关键和决定性作用的转录因子。GFI-1是维持骨髓中成人干细胞的功能完整性、中性粒细胞的产生和适当的淋巴发育所必需的。GFI-1b对于红系和巨核系的产生以及原始(卵黄囊来源)红系细胞的正确分化是必不可少的。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，它们显示出恶性特性。鉴于我们最近的发现将GFI-1和GFI-1b与染色质修饰物LSD1(赖氨酸特异性去甲基酶1)、Corest/Rcor1(REST共抑制物)、其他Rcor同源物和组蛋白去乙酰基酶HDAC1-2联系起来，我们建议探索这些辅助因子在与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单独和组合作用如何影响从早期个体发育到成年阶段的血细胞的形成、命运和功能。此外，我们还将研究这些蛋白及其辅助因子在多种细胞环境中选择和调节GFI-1/1b基因靶标的机制，并确定这些过程的生物学后果。这些实验将对哺乳动物造血发育的基本遗传和表观遗传编程产生有价值的见解和信息。这些见解将进一步成为理解LSD1和Rcor蛋白产生类似影响的其他发育系统的范例。此外，通过对这些因子正常功能的研究获得的见解将照亮我们对干细胞和祖细胞生物学的整体看法，无论是在正常条件下还是在血液病中。 与公共卫生相关：正常的血细胞生成对我们的生存和福祉至关重要；这一过程相对轻微的中断可能会导致虚弱和危及生命的情况，如贫血、血细胞减少、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合作者在血细胞生产中的正常功能也将揭示这些基因潜在的恶性特性。

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.