Toward Understanding the Role of the Polycomb Complex in Skin Control

项目摘要 本项目摘要/摘要与补编有关。毛囊干细胞具有 在生物体的一生中产生新毛囊的独特能力。当一个新的 毛囊出现时，hfscs被激活；它们增殖以促进新毛囊的产生并迅速恢复。 为了宁静。虽然在静止和激活之间的这种转变被调节的手段仍然存在 难以捉摸的是，这些过程的识别是至关重要的，因为HFSC的异常激活对头发有影响 丧失、衰老和癌症。 多梳抑制复合体(PRC)1和2是重要的染色质转录调节因子 用来维持干细胞的特性。通过进行功能丧失研究，我们发现在hfSCs中Prc1的丢失 会导致hfSCs过早激活并诱导毛发生长，而PrC2的丢失会导致 HFSC静息时间延长，毛发生长延迟。这些数据显示了关键和对立的角色 多梳复合体在调节HFSC静息中的作用。 R01家长基金的重点是研究Polycomb介导的调控过程，通过 HFSC被激活到静止状态。R01建议调查的三个目标：(1)调查 PRC2在HFSC激活和静止中的抑制作用；(2)研究PRC2和PRC2之间的冗余 2在激活和静止之间的微妙平衡；以及(3)检查任何潜在的非规范角色 在调节肾小管上皮细胞静息中的作用。 在这个补充应用中，我们建议研究Polycomb介导的作用 创伤愈合过程中hfSCs对干细胞命运转换的调控。这与R01家长资助有关，由 进一步调查中国参与的监管在世界粮食安全中心内的重要性及其关系 来维持HF特有的茎。伤口愈合是一个复杂但势在必行的生理过程 对于皮肤的动态平衡，它包括三个不同的阶段：炎症、再上皮化和重塑阶段。 在再上皮化阶段，毛囊内表皮干细胞(Ife)是主要的 损伤的表皮的贡献者。然而，血统追踪实验表明，HFSC源于 细胞也有助于损伤的表皮。最近，单细胞RNA测序分析显示 在损伤后，hfSCs经历转录转换，并获得IFE-SC转录信号。这 数据还显示，hfSCs还上调了与伤口基质相协调的蛋白质以进行迁移。这个 目前还不清楚这种转录开关或hfSCs的细胞命运不忠的调控。在这里，我们将 探讨在伤口愈合过程中，PRC1和PRC2在控制HF血统保真度中的作用。

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.