衰老过程中增强子调控细胞外基质（ECM）重塑影响表皮干细胞稳态的分子机制研究

表皮干细胞的再生能力随年龄增长而不断下降，从而引起皮肤老化和异常。增强子是染色质开放、富集H3K27乙酰化（H3K27ac）修饰的远端非编码DNA元件，能够加强特定基因表达，参与调控表皮干细胞增殖和分化。我们前期研究表明：在小鼠老化皮肤的表皮干细胞中，与基底膜相关的ECM基因表达显著下降，其远端调控增强子的染色质开放性减弱，表皮干细胞类群发生了明显改变。由此提出假想：衰老过程中ECM基因邻近增强子活性减弱，抑制ECM基因表达，引起ECM重塑，影响表皮干细胞与基底膜的互作及其稳态。本项目拟整合多组学数据，挖掘转录因子（TFs）/增强子/ECM基因转录调控互作网络的关键因子；通过分子、动物实验，验证ECM基因邻近增强子的开放性和活性减弱调控ECM基因表达，引起ECM重塑影响表皮干细胞稳态的分子机制。本项目将为进一步揭示皮肤组织稳态维持和衰老的机制并寻找潜在抗衰老药物提供理论依据。

The regeneration ability of epidermal stem cells (EpdSCs) gradually declines with age, eventually leading to the age-related decline of skin functions. Enhancers are non-coding DNA regulatory elements with high chromatin accessibility and histone H3K27 acetylation (H3K27ac). They play an essential role in EpdSCs proliferation and differentiation by fine-tuning the expression of the flanking genes. Our preliminary analyses demonstrated that the expression of ECM/basement membrane genes is down-regulated in EpdSCs. Besides, we observed the decreased chromatin openness of enhancers and the dramatic changes of the epidermal stem cell population in aged skin. Therefore, we hypothesis that the inactivation of enhancers might decrease the expression of ECM genes and trigger ECM remodeling, and eventually leads to the disruption of EpdSCs-ECM interaction and functional decline of EpdSCs in aged skin. Our study intends to prioritize critical regulators in the gene regulatory network involved transcription factors (TFs), enhancers and ECM genes in EpdSCs with age through integrating multi-omics datasets. Furthermore, we will experimentally validate the molecular mechanism that the openness and activity of ECM genes nearby enhancer disrupt epidermal stem cell homeostasis through ECM remodeling in aged skin. Thus, our study will lay an important foundation for further mechanistic investigations of skin homeostasis maintenance aging, and accelerating the anti-aging drug discovery.