My career goal is to direct an independent research group studying the nature and function of chromatin factors that control hematopoietic cell fate. My research background in epigenetic gene regulation plus my developing expertise in zebrafish genetics and hematopoiesis provide me with the knowledge to perform the proposed research. The training program in the hematology/oncology division at Children's Hospital and Harvard Medical School provides an outstanding environment for the completion of training during the mentored phase. This will greatly facilitate my smooth transition to independence. Research Description Hematopoiesis is controlled by complicated genetic programs involving tissue-specific transcription factors and chromatin remodeling factors. Understanding the regulatory mechanism of hematopoiesis provides significant insight into the pathophysiology of human blood malignancies such as leukemia. The transcription intermediary factor TIF1? is a critical factor for hematopoiesis yet the mechanism is not well understood. Through a large-scale genetic suppressor screen using the zebrafish TIF1? mutant, I identified two suppressor mutants that can bypass the requirement of TIF1? and restore blood in TIF1?-deficient animals. Initial characterizations of these mutants suggest a fundamental role of TIF1? in regulating transcriptional elongation and chromatin remodeling during hematopoiesis. The research described in this proposal is designed to elucidate the mechanism by which TIF1? regulates these processes.
Aim1 will use chromatin immunoprecipitation (ChIP) analyses to thoroughly examine the distribution of RNA polymerase II and associated histone markers on blood genes in TIF1?-deficient cells.
Aim2 will use the available conditional knockout mice to investigate the function of TIF1? and its suppressors in mammalian hematopoiesis.
Aim3 will focus on the in-depth characterization of the interaction between TIF1? and the cohesin chromatin remodeling complex using genetic and biochemical approaches. Completion of these aims will reveal the interplay among transcription factors, elongation factors and chromatin remodelers during hematopoiesis. Given the involvement of transcriptional elongation and chromatin modification in a variety of human disorders, these studies will advance our understanding of their roles in the pathogenesis and progression of these maladies and may also identify candidate genes or pathways that can be used for developing novel targeted treatment strategies.
Greater insight into the regulation of hematopoietic gene program will lead to improved treatment for hematologic disorders such as leukemia and anemia. By studying the epigenetic aspect of hematopoietic gene regulation, my research will advance our understanding of the mechanisms that controls blood formation and may identify novel regulators that will broaden possible therapeutic targets for blood diseases.