Remodeling the epithelial stem cell

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DESCRIPTION (provided by applicant): We have recently shown that the chromatin remodeler Mi-2b is critical for the self-renewal properties of the hematopoietic stem cell (HSC) and for the plasticity that allows its progeny to differentiate along the various lineages of the hematopoietic system. We now propose to extend this analysis to the stem cells of the hair follicle whose unique properties allow rigorous analysis of gene function in these cells and their derivatives. Our preliminary data show that Mi-2b is necessary for maintenance of the hair follicle in the adult. We will now exploit existing methods to delete Mi-2b specifically in two distinct follicular stem cell populations, the long-lived follicular bulge stem cell and the short-lived matrix stem cell. This approach will be augmented by techniques newly developed in the laboratory to target and purify these distinct stem cell types. We will characterize the effects of deleting Mi-2b in these populations and the molecular pathways affected. By comparing these with results already obtained in the hematopoietic system, we will gain insight into the common genetic cascades that control adult somatic stem cell behavior. Enzymes that remodel chromatin to regulate the accessibility of genes play a critical role in adult stem cells both by poising some genes for potential expression and by actively repressing the expression of others. We have previously demonstrated the role of the chromatin remodeler Mi-2b in the maintenance of the hematopoietic stem cell and differentiation of its progeny and identified the genes regulated in these cells. We propose to characterize the requirement for Mi-2b in another adult stem cell population, the keratinocyte stem cells of the adult hair follicle. By comparing the function of Mi-2b in these two different stem cells, we hope to identify common functions that are fundamental to stem cell behavior while identifying activities that are specific to these different types of stem cells.