Epigenetic control of stem cell activity during epithelial tissue regeneration

在组织工程时代和干细胞驱动的器官再生的新方法的发展中，研究人员和医生了解多能干细胞如何分化为特化细胞类型，以及为什么这些过程在病理条件下发生变化，如癌症、自身免疫疾病、受损的组织再生、伤口愈合和脱发。成年干细胞有助于健康有机体中许多器官的再生过程。然而，控制干细胞活动的机制在许多疾病中都会发生变化。因此，研究这些疾病与改变的机制之间的关系是生物医学研究的一个重要领域。皮肤是成体干细胞的重要来源，从皮肤中分离出的几种不同的成体体细胞群被成功地用于重新编程和产生诱导的多能细胞。过去二十年对基因组和染色质生物学的研究表明，除了遗传机制外，谱系特异的基因表达程序也受到表观遗传的调控，即通过染色质结构的生化修饰。多梳族蛋白是表观遗传调节因子，作为转录抑制因子，通过酶促组蛋白修饰来压缩染色质，并防止转录机制与基因启动子结合。多梳蛋白在控制皮肤上皮干细胞的更新和分化中起着关键作用。Cbx4是Polycomb家族的一员，在正常皮肤中保护上皮干细胞免受衰老。然而，它在伤口愈合过程中控制干细胞活性的作用尚不清楚。这项建议代表了目前由英国医学研究委员会、中国国家科学基金和英国-中国科学桥计划资助的两个实验室之间富有成效的合作的合乎逻辑的继续。这项建议将扩展这些研究，以确定多梳状抑制物Cbx4在创伤诱导再生期间控制皮肤干细胞活动中的作用。该项目的成功实施将有助于更好地了解在再生上皮组织中控制干细胞活动的调控机制的复杂性，并有助于设计新的方法，在伴随着干细胞不受控制的激活/扩张或耗尽/丢失的临床条件下如何靶向干细胞。

In the era of tissue engineering and the development of novel approaches for stem cell-driven organ regeneration, it is important for researchers and physicians to understand how multi-potent stem cells differentiate into specialized cell types, and why these processes are altered in pathological conditions, such as cancer, autoimmune conditions, impaired tissue regeneration, wound healing, hair loss.Adult stem cells contribute to the regeneration process of many organs in a healthy organism. The mechanisms that control stem cell activity, however, are altered in many disorders. Research into the relationship between these disorders and the changed mechanisms is, thus, an important area for biomedical research. Skin serves as an important source of adult stem cells, and several distinct adult somatic cell populations isolated from the skin were successfully employed for reprogramming and generation of induced pluripotent cells. Research into genome and chromatin biology over the last two decades has revealed that in addition to genetic mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via biochemical modification of the chromatin structure. Polycomb group proteins are epigenetic regulators that operate as transcriptional repressors, compacting chromatin via enzymatic histone modifications and preventing binding of the transcription machinery to gene promoters. The polycomb group proteins play a critical role in the control of epithelial stem cell renewal and differentiation in the skin. Cbx4 as a member of Polycomb family of proteins protects epithelial stem cells from ageing in normal skin. However, its role in the control of stem cell activity during wound healing remains unclear. This proposal represents a logical continuation of productive collaboration between two laboratories currently supported by the grants from the Medical Research Council UK, National Science Foundation of China and UK-China Science Bridge Programme. This proposal will extend these studies to define the role of Polycomb repressor Cbx4 in the control of stem cell activity in the skin during wound-induced regeneration. Successful performance of this project will help in better understanding the complexity of regulatory mechanisms that control stem cell activity in regenerating epithelial tissues and in designing new approaches on how to target stem cells in the clinical conditions accompanied by their un-controlled activation/expansion or exhausting/loss.