Zfp42通过节律基因调控表皮干细胞抗衰老的作用和机制

表皮干细胞（EPSCs）的持续自我更新和分化维持表皮稳态，构成皮肤最外层的防御机制。随着年龄增长，EPSCs干性的下降造成皮肤衰老及疾病增加。目前的表皮抗衰老研究集中在提高EPSCs的干性而具体机制不明。通过比较胎儿和成人EPSCs的基因组学，我们筛选出在胎儿EPSCs富集的Zfp42，证实其下调能抑制EPSCs的增殖，促进其分化。ChIP-seq分析，发现Zfp42在节律基因PER2和CRY1的启动子区域有结合位点。我们推测Zfp42通过调控节律基因参与成人EPSCs的衰老。本课题拟在细胞和在体人皮肤移植模型中确定Zfp42过表达对成人EPSCs的干性的促进作用，并在分子、细胞和动物模型层面上，阐明Zfp42作用的靶点及机制，明确Zfp42通过调控节律基因影响EPSCs的衰老的作用。本项目将有助于全面深入地了解成人EPSCs衰老的机制，为开发新的抗衰老药物靶点提供理论基础。

Epidermal homeostasis is the maintained by the constant epidermal self-renewal and differentiation of epidermal stem and progenitor cells (EPSCs) throughout life since epidermis is the outmost layer of the skin and an important defense system to the environment. As ageing, the stemness of EPSCs decrease which result skin ageing and disease. Current anti-ageing therapeutic strategies focus on increasing the stemness of EPSCs. Our preliminary data has shown that Zfp42 is highly expressed in fetal EPSCs compared to adult EPSCs. Its downregulation inhibits the self-renewal and promotes differentiation in neonatal EPSCs. Zfp42 is known as an embryonic stem cell marker and also expresses in adult stem cells and cancer cells. However, its role in EPSCs is unknown. Our preliminary ChIP-seq data has found Zfp42 peaks at the promoter region of circadian genes including PER2 and CRY1 and downstream regulator MYC. We hypothesized that Zfp42 may exhibit its anti-ageing effect in adult EPSCs through regulating circadian genes. Next, we will characterize the effect of Zfp42 overexpression in adult EPSCs using both in vitro and in vivo skin graft model. We will identify the downstream targets and mechanisms of Zfp42 through RNA-seq, ChIP-seq and Co-IP mass spec. This study will elucidate the mechanism of adult EPSCs ageing and provide potential therapeutic targets for anti skin ageing drug in clinic.