Mechanisms of Lymphocyte Gene Regulation by E2A and Notch1

淋巴细胞发育生物学中的一个突出问题是具有多种分化选择的细胞如何被限制于单一的发育命运。了解B和T淋巴细胞谱系限制是如何发生的也是临床相关的，因为这些程序中的错误可能导致严重的疾病，如免疫缺陷或白血病淋巴瘤。因此，为了设计有效的治疗方法来干预疾病，并预测治疗干预对淋巴细胞发育的影响，我们需要对控制淋巴细胞生成的因素有一个机械的理解。E2 A转录因子是B-和1-淋巴细胞发育的重要调节因子。Notchi受体对于促进T淋巴细胞生成是必需的，但抑制B淋巴细胞生成，并且已经表明通过抑制E2 A发挥作用。尽管如此，E2 A和/或Notch信号传导如何起作用以促进B-或1-淋巴细胞命运仍然是淋巴细胞发育中的主要问题。在这里，我们提出的实验，以确定如何E2 A和Notch 1有助于淋巴祖细胞的基因表达。在目的1中，我们将检验E2 A仅在组蛋白的转录后修饰导致“开放”染色质状态后才与必需B淋巴细胞转录因子早期B细胞因子（Ebfl）的启动子结合的假设。在目标2中，我们将测试Notchi抑制CcrQ的假设，CcrQ是一种趋化因子受体，其适当的调节是T细胞发育所必需的，通过Hesiindependent机制，我们的实验将提供重要的洞察淋巴细胞发育的分子机制，以及该过程的两个关键调节因子如何建立适当的谱系特异性基因程序。

An outstanding question in lymphocyte developmental biology is how a cell with multiple differentiation options becomes restricted to a single developmental fate. Understanding how B- and T-lymphocyte lineage restriction occurs is also clinically relevant since mistakes in these programs can lead to severe disease such as immune deficiency or leukemialymphoma. Therefore, to design effective therapies to intervene in disease and to predict the effects of therapeutic intervention on lymphocyte development we need to gain a mechanistic understanding of the factors that control lymphopoiesis. The E2A transcription factors are essential regulators of both B- and 1-lymphocyte development. The Notchi receptor is essential for promoting T-lymphopoiesis but suppresses B - Iymphopoiesis and has been suggested to function through repression of E2A. Nonetheless, how E2A and/or Notch signaling function to promote the B- or 1- lymphocyte fate remains a major question in lymphocyte development. Here we propose experiments to determine how E2A and Notch 1 contribute to gene expression in lymphoid progenitors. In Aim 1 we will test the hypothesis that E2A binds to the promoter of the essential B-lymphocyte transcription factor early B cell factor (Ebfl) only after post-transcriptional modification of histones that lead to an "open" chromatin state. In Aim 2 we will test the hypothesis Notchi represses CcrQ, a chemokine receptors whose proper regulation is essential for T-cell development, through a Hesiindependent mechanism, Our experiments will provide important insight into the molecular mechanisms underlying lymphocyte development and how two critical regulators of this process set up an appropriate lineage specific gene program.