Molecular Regulation of Mammalian Erythro-Megakaryocytic Development

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Erythroid (E; red blood cell) and megakaryocytic (M; platelet precursor) lineages are essential and vital to vertebrate health and viability as they performing crucial functions like oxygen delivery and wound healing. Consequently, relatively minor aberrations in their developmental or functional programs lead to life threatening disorders. These proclivities are an inevitable fall out of the high turnover rate of these cells that makes them acutely susceptible to malfunctions and malignancies arising from imbalances between proliferation and differentiation. These imbalances in turn are due to the dysfunctions of various molecular regulators of these processes as evidenced by a growing body of data from human patients and animal models. The transcriptional repressors Gfi1/1b (growth factor independence 1/1b) and their cofactors LSD1 (lysine specific demethylase1) and Rcor (REST corepressor) proteins have emerged over the past several years as critical regulators of hematopoiesis. Yet the true scale of their functions, and mechanistic ramifications of their actions, in E-M development have only been nominally documented. Therefore, this proposal focuses on elucidating the collective functions of these transcriptional and chromatin regulators and their principal gene/chromatin targets, in orchestrating the ontogeny of E-M cells from progenitor (MEP) specification to their divergence and differentiation into specialized effector cells. In addition to producing a comprehensive overview of these emergent molecular programs and networks in normal development, these insights should also provide a rational scientific basis for managing hematopoietic disorders resulting from the errant activities of these master molecules.