I am a Ruth L. Kirschstein National Research Service Award postdoctoral fellow in Dr. Michael Snyder's lab at Yale University. My previous training focused on molecular genetics and genomics, specifically genome-wide transcriptional mapping and novel gene characterization. During the proposed career development I will obtain in-depth training in hematopoiesis, functional genomics, proteomics, large-scale data integration and network construction on both experimental and computational levels. The excellent training environment in the Yale Center for Genomics and Proteomics in combination with my co-mentor Dr. Sherman Weissman and advisory committee's expertise in hematopoietic stem cell biology is uniquely suited for me to launch an independent academic research career in cell self-renewal and differentiation. The goal of my five-year research plan is to generate a novel and comprehensive view of cell self-renewal and differentiation by using integrated genomic and proteomic approaches and murine EML (Erythroid, Myeloid, and Lymphocytic) multipotential hematopoietic precursor cells as a primary model. EML cells are ideal for studying the molecular control of early hematopoietic differentiation at a large scale. EML cells give rise to the self-renewing CD34+ precursor cells and partially differentiated non-renewing CD34- cells. Large quantities of EML cells can be grown and differentiated in vitro in the absence of an anatomical niche. Based on my preliminary study of differential gene expression profiling, and of transcription factor binding using Chip-chip, I hypothesize that there are key regulators (such as: TCF7, RUNX1 and GATA2) in transcriptional regulatory networks that determine the choice between EML cell self-renewal and differentiation. Specifically, I propose to globally identify the key transcriptional regulators controlling these processes by using gene expression and proteomic data to guide the transcriptional regulation work. The binding targets and transcription factors will be assembled into regulatory networks, and I will identify target hubs and test for master regulators. Subsequently I will integrate our genomic, proteomic, phosphorylation data and literature into the transcription factor binding networks and further develop a global interaction network. Finally I will confirm key findings in human hematopoietic precursor cells.
These studies in EML cells will demonstrate fundamental properties of self-renewal and differentiation mechanisms available to stem cells which hold great promise in repairing or regenerating damaged tissues and organs. Molecular understanding gained through this study will hopefully improve our ability to direct hematopoietic stem cell fate by, for example, replicating and differentiating HSCs in vitro. Therefore, this study is highly valuable for public health and therapeutic purposes for leukemia.
|Zong, Shan; Deng, Shuyun; Chen, Kenian et al. (2014) Identification of key factors regulating self-renewal and differentiation in EML hematopoietic precursor cells by RNA-sequencing analysis. J Vis Exp :e52104|
|Wu, Jia Qian; Seay, Montrell; Schulz, Vincent P et al. (2012) Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS Genet 8:e1002565|