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

项目摘要 在成年人中，皮肤不断自我更新，皮肤基底层的干细胞（EpSC） 毛囊间上皮和毛囊干细胞（HFSC）驻留在毛囊隆突负责 用于在损伤后维持组织完整性、结构和上皮再生。然而，在生物体的 这些成年人皮肤的SC池要么失去活力，要么数量减少，这表现为衰老。 相关的表型，包括表皮萎缩，脆性，脱发疾病和延迟伤口愈合。的 在成人皮肤中驱动SC老化的基本机制在很大程度上仍然未知。 到目前为止，对无脊椎动物和细胞衰老模型的研究表明， 许多组蛋白甲基化的占据以及甲基转移酶和去甲基化酶的调节增加 有机体寿命虽然大多数这些研究为我们了解表观遗传如何 机制影响衰老过程，需要解决这些机制是否也有助于 哺乳动物组织的老化。我的初步体内功能丧失研究表明， 表观遗传调节因子，多梳抑制复合物（PRCs），可能在HFSC中发挥差异作用 和EpSCs来维持它们在成人皮肤中的寿命。这一点特别有趣，因为 全基因组研究表明，老年HFSC中染色质可及性的调节建立了一种新的免疫调节机制。 促进衰老的转录景观。该提案的目的是增加这些相关的 观察并阐明表观遗传调节因子及其相应的组蛋白修饰是否具有 保护SC在皮肤中的寿命的功能作用。为此，本提案的具体目标是： 将联合收割机功能性体内遗传模型与最先进的多组学方法相结合，以： 1)表征不同SC的转录和染色质景观的年龄依赖性变化， 成年人皮肤的凹陷; 2)测试Polycomb依赖性机制在维持寿命和再生中的功能作用 成人皮肤SC的容量;以及 3)建立一个功能相关性，即SC染色质状态的年龄依赖性变化促进衰老- 相关表型 这项建议的结果将大大加强我们对年龄依赖性变化的理解， 表观遗传机制建立了一个转录景观，促进SC老化，并将提供新的 在衰老相关疾病治疗中转化研究应用的科学途径， 紊乱

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.