Toward Understanding the Role of the Polycomb Complex in Skin Control

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Project Summary This project summary/abstract pertains to the supplement. Hair follicle stem cells (HFSCs) have the unique ability to generate new hair follicles throughout the lifetime of an organism. When the growth of a new hair follicle occurs, HFSCs are activated; they proliferate to fuel the production of a new follicle and quickly return to quiescence. While the means by which this transition between quiescence and activation is regulated remain elusive, identification of these processes is critical, because abnormal HFSC activation has implications in hair loss, aging, and cancer. Polycomb repressive complexes (PRC) 1 and 2 are chromatin transcriptional regulators that are essential for maintaining stem cell identity. By performing loss-of-function studies, we showed that loss of PRC1 in HFSCs results in premature activation of HFSCs and the induction of hair growth, whereas loss of PRC2 leads to a prolonged HFSC quiescence and delayed hair growth. These data show the critical and opposing roles of Polycomb complexes in the regulation of HFSC quiescence. The R01 parent grant focuses on investigating the Polycomb-mediated regulatory processes by which HFSC activation to quiescence occurs. The R01 suggests three aims for investigation: (1) Investigate the repressive roles of PRC2 in HFSC activation and quiescence; (2) study the redundancy between both PRC1 and 2 in the delicate balance between activation and quiescence; and (3) examine any potential noncanonical roles of PRC1 in regulating quiescence in the HFSC. In this supplemental application, we are proposing to investigate the roles of Polycomb-mediated regulation in the stem cell fate switch of HFSCs during wound healing. This relates to the R01 parent grant by furthering the investigation of the importance of PRC-mediated regulation within the HFSC and its relationship to the maintenance of HF-specific stemness. Wound healing is a complex but imperative physiological process for skin homeostasis and involves three distinct stages: inflammation, re-epithelization, and remodeling stages. During the re-epithelialization stage, it is known that intrafollicular epidermal (IFE) stem cells (SCs) are the major contributors to the wounded epidermis. However, lineage-tracing experiments have revealed that HFSC derived cells also help contribute to the wounded epidermis. Recently, single-cell RNA-sequencing analysis showed upon wounding, HFSCs undergo a transcriptional switch and acquire an IFE-SC transcriptional signature. This data also revealed that HFSCs also upregulate proteins that coordinate with wound stroma for migration. The regulation of this transcriptional switch or cell fate infidelity of the HFSCs is currently unknown. Here, we will explore the roles of PRC1 and PRC2 in controlling HF lineage fidelity during wound healing.