Transcriptional Regulatory Networks Active in Terminal Erythroid Differentiation

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DESCRIPTION (provided by applicant): As a pediatric hematologist, I feel a great need to understand the mechanisms behind the dysregulation of differentiation and proliferation that occur in certain acquired and congenital aplastic anemias and leukemias found in my patient population. The most that modern medicine can often offer these patients is bone marrow transplant. I pursue a career in basic laboratory science in hematology with this quandary in mind, and thus aim to understand the regulation of erythropoiesis. I envision this current research project as intensive training in the biology, research techniques, and information manipulation that are required of an independent investigator in this field, while at the same time, uncovering possible novel genes or new insight into the process of differentiation itself. The research environment, outstanding mentorship, and resources in the form of collaborators, equipment, classes, and colleagues at the Dana Farber Cancer Institute and the Whitehead Institute will uniquely assist me in achieving my career goals. Erythropoietin (Epo) and its cognate receptor, EpoR, ensure the survival of early erythroid precursors in part through induction of the anti-apoptotic protein bcl-xL by the Signal transducer and activator of transcription 5 (Stat5). Epo binding to EpoR results in activation of several signal transduction pathways including the Phosphatidylinositol 3 kinase (Pi3K)/AKT kinase, ras/Mitogen-Activated Protein Kinase (MAPK), and Stat5 pathways, which also initiate the erythroid-specific expression and cellular programs that establish the erythroid phenotype. However, these pathways are not unique to the erythroid lineage: Stat5 activation occurs downstream of numerous cytokine receptors in diverse tissues, regulating vastly different tissue phenotypes. Presumably, these generic, cytokine-induced transcription factors require interaction with pre-existing tissue-specific factors in order to exert their function. Erythroid-important regulatory proteins, GATA1 and FOG (friend of GATA1), are also known to be essential for normal erythropoiesis. In order to elucidate how cytokine-activated and tissue-specific regulatory proteins can collectively initiate the unique expression programs of a tissue, I intend to determine the direct targets of Stat5, GATA1, and FOG in distinct stages of differentiation using chromatin immunoprecipitation and promoter microarrays. I plan to use innovative bioinformatics strategies as well as expression profiling to validate my location data and establish an outline for the transcriptional regulation of erythropoiesis. How genes instruct proteins in different cell types to become unique tissues is probably the basis for how this instruction can go awry in diseases like anemias and leukemias. I plan to understand this program in the biology of red blood cell development, in hopes of discovering new treatments for these disorders.