Mechanisms of endothelial-to-hemogenic transition mediated by Runx1

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Project Summary Hematopoietic stem and progenitor cells (HSPCs) differentiate from specialized endothelial cells in the embryo called hemogenic endothelium (HE). The transcription factor Runx1 is required for the specification of hemogenic endothelium and for the endothelial to HSPC transition to occur. However, how Runx1 does so is poorly understood. Our goal is to apply systems biology approaches to study the transcriptional regulatory network controlling hemogenic endothelial specification, including the role of Runx1, additional transcription factors that cooperate with Runx1, and the order of regulatory events that promote the process. These studies will not only increase our understanding of the normal developmental process of HSPC formation, but will help guide attempts to generate hematopoietic stem cells (HSCs) from endothelial cells, ES, or iPS cells for the treatment of disease. In Aim 1, we will identify Runx1 target genes in embryonic endothelial cells that are competent to respond to Runx1, and examine the genome-wide chromatin modifications and gene expression changes that take place when Runx1 binds its target genes. In Aim 2, we will develop an advanced graph-theoretic method to identify key TFs that cooperate with Runx1 in embryonic endothelial cells to induce HE and form blood. We will validate the candidate TFs by determining their ability to cooperate with Runx1 to induce fetal endothelial cells to undergo endothelial to HSPC transition and form blood.