Mechanisms of Lymphocyte Gene Regulation by E2A and Notch1

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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.