Mechanisms of Lymphocyte Gene Regulation by E2A and Notch1

淋巴细胞发育生物学中的一个悬而未决的问题是，拥有多种分化选择的细胞如何变得受限于单一的发育命运。了解B和T淋巴细胞谱系限制是如何发生的也具有临床意义，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，要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，我们需要从机制上了解控制淋巴细胞生成的因素。E2a转录因子是B淋巴细胞和1淋巴细胞发育的重要调节因子。Notchi受体对促进T淋巴细胞生成是必不可少的，但抑制B淋巴细胞生成，并被认为是通过抑制E2a发挥作用。尽管如此，E2A和/或Notch信号如何促进B或1淋巴细胞的命运仍然是淋巴细胞发育中的一个主要问题。在这里，我们建议进行实验，以确定E2A和Notch 1如何对淋巴祖细胞的基因表达做出贡献。在目标1中，我们将检验这样的假设，即只有在组蛋白转录后修饰导致染色质状态开放之后，E2A才与必要的B淋巴细胞转录因子早期B细胞因子(Ebf1)的启动子结合。在目标2中，我们将检验Notchi抑制CcrQ的假设，CcrQ是一种趋化因子受体，其适当调节对T细胞发育至关重要，我们的实验将通过一个高度独立的机制提供重要的见解，以了解淋巴细胞发育的分子机制，以及这一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.