Transcriptional Control of Hematopoiesis

描述（申请人提供）：生物学中两个悬而未决的问题是干细胞自我更新是如何被控制的，以及具有多种分化选择的细胞如何被限制为单一的发育命运。造血系统是研究这些问题的一个极好的模型，因为它来源于一个干细胞库，在整个生命过程中维持至少8种不同细胞系的产生。这个模型也具有临床意义，因为造血干细胞是骨髓移植的基础，在这个发育过程中出现错误可能导致严重的疾病，如免疫缺陷或白血病。因此，为了设计有效的治疗方法来干预疾病，并预测治疗干预对造血发育的影响，我们需要对控制造血的因素有一个机制上的了解。E蛋白转录因子是脊椎动物和无脊椎动物细胞命运的重要调节因子，并与涉及造血干细胞（HSC）发育和功能的多种蛋白相互作用。尽管如此，E蛋白在造血干细胞或早期造血细胞命运决定中的作用直到最近才得到证实。我们已经确定由E2A基因编码的E蛋白是造血干细胞正常维持所必需的，它们支持多能祖细胞向淋巴系的初始规范。在本申请的目的1中，我们提出了实验来验证E2A蛋白在移植后骨髓再生过程中促进HSC自我更新的假设。我们还将检验E2A缺陷造血干细胞不能适当地回到造血干细胞生态位和/或不能保留在生态位内的假设。在目标2中，我们将检验淋巴样物质规范需要E蛋白同型二聚体的假设，并确定控制同型二聚体形成的机制。在解决这些假设时，我们将对造血干细胞功能和向淋巴系分化的分子机制获得重要的见解。此外，由于E蛋白拮抗剂可以通过信号通路调节，例如转化生长因子-21或骨形态发生蛋白，我们的研究结果可能揭示了这些通路影响造血的机制。公共卫生相关性：造血异常控制是许多疾病的潜在原因，包括免疫缺陷、贫血、自身免疫和白血病或淋巴瘤。我们研究的目的是确定控制造血的分子机制，特别强调向淋巴谱系分化。我们的研究将揭示E蛋白转录因子维持造血干细胞功能和促进淋巴系分化的机制。

DESCRIPTION (provided by applicant): Two outstanding questions in biology are how stem cell self-renewal is controlled and how a cell with multiple differentiation options becomes restricted to a single developmental fate. The hematopoietic system is an excellent model to study these questions owing to its derivation from a pool of stem cells that maintains production of at least eight distinct cell lineages throughout life. This model is also clinically relevant because HSCs are the foundation for bone marrow transplantation and mistakes in this developmental program can lead to severe disease such as immune deficiency or leukemia. Therefore, to design effective therapies to intervene in disease and to predict the effects of therapeutic intervention on hematopoietic development we need to gain a mechanistic understanding of the factors that control hematopoiesis. The E protein transcription factors are essential regulators of cell fate in vertebrates and invertebrates and interact with multiple proteins implicated in hematopoietic stem cell (HSC) development and function. Nonetheless, a role for E proteins in HSCs or in early hematopoietic cell fate decisions has only recently been demonstrated. We have determined that the E proteins encoded by the E2A gene are required for proper maintenance of HSCs and they support the initial specification of multipotent progenitors toward the lymphoid lineages. In Aim 1 of this application we propose experiments to test the hypothesis that E2A proteins promote HSC self-renewal during regeneration of bone marrow following transplantation. We will also test the hypothesis that E2A- deficient HSCs fail to home appropriately to the HSC niche and/or fail to be retained within the niche. In Aim 2 we will test the hypothesis that lymphoid specification requires E protein homodimers and we will determine the mechanisms controlling homodimers formation. In addressing these hypotheses we will gain important insight into the molecular mechanisms underlying hematopoietic stem cell function and differentiation toward the lymphoid lineages. Moreover, since E protein antagonists can be modulated by signaling pathways, for example transforming growth factor-21 or bone morphogenic proteins, our results may reveal mechanisms by which these pathways can influence hematopoiesis. PUBLIC HEALTH RELEVANCE: Aberrant control of hematopoiesis is the underlying cause of many diseases including immune deficiency, anemia, autoimmunity and leukemia or lymphoma. The goal of our research is to determine the molecular mechanisms that control hematopoiesis with a particular emphasis on differentiation toward the lymphoid lineages. Our study will reveal the mechanisms by which E protein transcription factors maintain hematopoietic stem cell function and promote differentiation toward the lymphoid lineages.