Role of the Polycomb group gene Cbx4 in the control of skin regeneration and wound healing

皮肤是覆盖身体的器官，保护我们免受各种环境侮辱，如机械损伤、微生物入侵、紫外线照射，还能防止水分流失。为了实现这一重要功能，皮肤必须在人的一生中不断地自我再生，而皮肤的这种自我再生能力依赖于表皮和毛囊中存在的上皮干细胞的正常功能，表皮和毛囊是皮肤的主要上皮结构。这些干细胞是长寿细胞，同时产生短命的特化后代，形成所有保护性的表皮细胞层和毛发。随着皮肤的老化，干细胞的功能活动会下降，导致表皮变薄和脱发，并降低它们在受伤后再生皮肤的能力。在过去的十年中获得的数据表明，有多个细胞生化途径控制皮肤干细胞的活性，最近的数据表明，这些生化途径的活性可以由表观遗传调节机制控制。这种表观遗传机制之一是组蛋白的修饰，组蛋白是与DNA密切相互作用的蛋白质，由多梳蛋白抑制基因的表达，从而改变许多重要的细胞功能。本项目将研究多梳基因Cbx4是如何影响正常的生理和损伤诱导的再生的。我们还将探讨Cbx4如何调节上皮干细胞及其后代(形成表皮和毛发的干细胞)中的不同分子信号，以及它们参与伤口愈合的过程。此外，我们还将研究Cbx4如何控制皮肤干细胞的长期存活及其产生皮肤特异性后代的能力。以这种方式研究皮肤作为模型系统，将有助于揭示控制其他上皮组织的发育和再生的机制，如肠、牙齿、肾脏和肺的上皮。因此，从这项研究中获得的知识将为开发新的表观遗传疗法提供新的机会，旨在防止组织异常生长和再生限制，如糖尿病患者和老年人的伤口愈合受损。

The skin is an organ that covers the body and protects us from a variety of environmental insults, such as mechanical injury, invasion of microorganisms, ultra-violet irradiation and also prevents water loss. To fulfil such important function, skin has to constantly regenerate itself throughout of a person's life, and this ability of the skin for self-regeneration relies on proper functioning of epithelial stem cells present in the epidermis and hair follicles, the major epithelial structures of the skin. These stem cells are long-living cells, while producing short-living specialised progenies that form all protective epidermal cell layers and hairs. As the skin ages, functional activities of the stem cells decline leading to a thinning of the epidermis and hair loss, as well as reducing their ability to regenerate the skin after injury. Data obtained during the last decade have revealed that there are multiple cellular biochemical pathways controlling skin stem cells activity, with recent data demonstrating that activity of these biochemical pathways can be governed by epigenetic regulatory mechanisms. One of such epigenetic mechanisms is the modification of histones, proteins closely interacting with DNA, by the Polycomb group proteins to repress the expression of genes and thus change many important cellular functions.This project will look at how a Polycomb group gene Cbx4, which represses many genes, impacts on normal physiological and injury-induced regeneration. We will also explore how Cbx4 regulates different molecular signals in the epithelial stem cells and their progenies (those which form the epidermis and hair), and their involvement in wound healing. In addition, we will examine how Cbx4 controls long-term survival of the skin stem cells and their ability to produce skin-specific progeny.Studying the skin as a model system in this way, will cast light on the mechanisms that control the development and regeneration of other epithelial tissues, such as the epithelia of the intestine, teeth, kidney and lung. The knowledge gained from this study will therefore provide new opportunities to aid in the development of novel epigenetic therapies intended to prevent aberrant tissue growth and regenerative limitations, such as impaired wound healing in diabetic patients and in elderly individuals.