The role of chromatin regulation in normal and cancer stem cell self-renawal

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DESCRIPTION (provided by applicant): Stem cells (both normal and cancerous) are defined by their ability to self-renew, in order to maintain their numbers, and their ability to differentiate into distinct cell types. Because of these competing functions, the genome of stem cells must be uniquely regulated-stem cells must stably maintain their gene expression pattern during self-renewal, but must be flexible enough to drastically alter their gene expression pattern during differentiation. The gene expression patterns of stem cells are regulated by transcription factors and chromatin regulators expressed in the cell. While transcription factors that control stem cell self-renewal vary considerably between different types of stem cells, there is increasing evidence that chromatin regulators of self-renewal function more broadly. Recently I performed an RNAi screen for chromatin regulators with important functions in embryonic stem cells and found 68 genes with an array of knockdown phenotypes. I will now screen these factors for function in a different stem cell type, cancer stem cells. Using both mouse models and human cancer cell lines, I will identify chromatin regulators of cancer stem cells, with the goal of identifying novel targets for more effective therapies that target the cancer stem cells. In addition, I will examine the stem cell-specific functions of one group of chromatin regulators identified in the embryonic stem cell screen, the condensin complexes. While condensins have known functions in all cell types, embryonic stem cells are acutely sensitive to their loss. Preliminary data indicates that these factors have previously unknown functions unique to stem cells. I will now characterize these functions. Finally, I will use methodology I developed for knocking down chromatin regulators in embryonic stem cells to examine the functional interactions of transcription factors and chromatin regulators. During the mentored phase of the award, I will carry out the screen of chromatin remodelers in cancer stem cells, which will generate many avenues of research that will be pursued during the independent phase. In addition, I will learn new techniques and participate in career development programs that will assist me in becoming an independent scientist and obtaining an independent position at an academic research institution. RELEVANCE: While normal stem cells hold promise for the development of therapies for regenerative diseases, cancer stem cells present a difficult challenge for traditional cancer therapies. Therefore, an understanding of how stem cells (normal and cancerous) maintain their identity would be beneficial for both regenerative medicine and identification of new therapies. Here I will examine how different stem cells are maintained.