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.
|Krishnamoorthy, Veena; Carr, Tiffany; de Pooter, Renee F et al. (2015) Correction: Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the notch signaling pathway. J Immunol 194:6191|
|Carr, Tiffany; Krishnamoorthy, Veena; Yu, Shuyang et al. (2015) The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation. J Exp Med 212:793-807|
|Krishnamoorthy, Veena; Carr, Tiffany; de Pooter, Renee F et al. (2015) Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway. J Immunol 194:3191-200|
|Gounari, Fotini; Kee, Barbara L (2013) Fingerprinting ikaros. Nat Immunol 14:1034-5|
|Xu, Wei; Carr, Tiffany; Ramirez, Kevin et al. (2013) E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121:1534-42|
|de Pooter, Renee F; Kee, Barbara L (2010) E proteins and the regulation of early lymphocyte development. Immunol Rev 238:93-109|