The roles of histone deacetylases 1 and 2 in epidermal development and adult tissue maintenance

The skin is the most common site of human malignancies. Skin malignancies may arise from or adopt characteristics of progenitor cell populations in the interfollicular epidermis and hair follicle. Understanding progenitor cell development and maintenance in normal tissues will provide insights into the mechanisms of epidermal disease and suggest novel therapeutic applications. Broad acting histone deactylase inhibitors are under investigation to treat a wide spectrum of diseases, including malignancies of the skin and other epithelia. However, the functions of specific HDAC proteins in embryonic development, adult tissue homeostasis, and disease are not well understood. In this dissertation, I use mouse genetics to analyze the roles of Hdac1, Hdac2, Foxp1, and Foxp4 in the embryonic epidermis and adult epidermis and hair follicles. These studies reveal redundant requirements for Hdac1 and Hdac2 in maintaining embryonic epidermal progenitor cells and adult stem cell populations by modulating p63 and p53 functions. In addition, they identify multiple transcription factors including p63, RXRα, FOXP1, and FOXP4 that act by targeting HDAC-containing complexes to specific gene targets. These findings provide insight into HDAC function in normal tissue biology, and a framework for understanding HDAC biology in epidermal and hair follicle disease