Identifying epigenetic factors in control of epidermal stem cell longevity in the adult skin

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Project Summary In adults, the skin constantly renews itself and the stem cells (SCs) of the basal layer (EpSCs) of the interfollicular epithelium and the hair follicle stem cells (HFSCs) residing in the hair follicle bulge are responsible for maintaining tissue integrity, structure, and reepithelization following an injury. However, over an organism’s lifetime these SC pools of the adult skin either lose their vigor or diminish in numbers which manifests into aging- related phenotypes that include epidermal atrophy, fragility, hair loss disorders and delayed wound healing. The fundamental mechanisms that drive SC aging in the adult skin remain largely unknown. To date research in invertebrate and cellular models of aging have shown that there is a change in global occupancy of many histone methylations, and modulation of methyltransferases and demethylases increase organism longevity. While most of these studies have paved the way for us to understand how epigenetic mechanisms influence the aging process, there is a need for addressing if these mechanisms also contribute towards aging of a mammalian tissue. My preliminary in vivo loss-of-function studies indicate that the conserved epigenetic regulators, Polycomb repressive complexes (PRCs), may be functioning differentially in the HFSCs and EpSCs to maintain their longevity in the adult skin. This is particularly intriguing in light of the fact that genome-wide studies have implicated that the modulation of chromatin accessibility in aged HFSCs establish a transcriptional landscape that promotes aging. The goal of this proposal is to add to these correlative observations and elucidate if epigenetic regulators and their corresponding histone modifications have a functional role in safeguarding SC longevity in the skin. To this end, the Specific Aims of this Proposal seek to combine functional in vivo genetic models with state-of-the-art multi-omics approaches to: 1) Characterize the age-dependent changes in transcriptional and chromatin landscape of the various SC pools of the adult skin; 2) Test the functional role of Polycomb-dependent mechanisms in maintaining the longevity and regenerative capacity of adult skin SCs; and 3) Establish a functional correlation that age-dependent changes in the SC chromatin state promotes aging- associated phenotypes. The results of this Proposal will significantly enhance our understanding of how age-dependent changes in epigenetic mechanisms establish a transcriptional landscape that promotes SC aging and will provide new scientific avenues for translational research application in the treatment for aging-associated conditions and disorders.