Genetic and Epigenetic Regulation of Hematopoiesis.

描述（由申请人提供）：造血，即血细胞的产生，是一种重要的、必不可少的发育现象，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包括人类在内的许多动物物种的生存和福祉至关重要；这一过程即使受到轻微破坏，也可能导致衰弱和危及生命的疾病，如贫血、细胞减少症、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广泛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。本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人造血的基本原理和事件。Gfi-1 （growth factor independence-1）和Gfi-1b是在哺乳动物造血过程中起重要决定性作用的转录因子。Gfi-1对于维持骨髓中成体干细胞的功能完整性、中性粒细胞的产生和适当的淋巴细胞发育是必需的。Gfi-1b对于红细胞和巨核细胞谱系的产生以及原始（卵黄囊衍生的）红细胞的正常分化至关重要。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，它们表现出恶性特性。鉴于我们最近的发现将Gfi-1和Gfi-1b与染色质修饰因子LSD1（赖氨酸特异性去甲基化酶1）、CoREST/Rcor1 （REST协同抑制因子）、其他rfi同源物和组蛋白去乙酰化酶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及其辅助因子在多种细胞环境下对Gfi-1/1b基因靶点的选择和调控机制，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。这些见解将进一步成为理解LSD1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获得的见解将照亮我们在正常条件下和血液疾病中干细胞和祖细胞生物学的整体视角。

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.