DNA hydroxymethylation, TET enzymes and regulation of stem cell activity during skin regeneration and wound healing

调节包括人类在内的哺乳动物发育的生物机制在人的一生中持续存在，并在衰老过程中发生变化。作为覆盖身体的器官，皮肤保护我们免受各种环境侮辱，如机械损伤、紫外线照射和温度变化。皮肤还提供了一个独特的系统，用于研究控制器官发育、再生和衰老的机制。皮肤的发育导致表皮的形成，表皮是一种层叠的自我更新的上皮。皮肤的其他结构包括毛囊、指甲和腺体。出生后，表皮利用上皮干细胞的能力不断再生，提供形成所有表皮细胞层的后代细胞。同时，皮肤损伤后的表皮再生是由来自毛囊的干细胞控制的。过去十年的数据表明，许多细胞生化途径控制着皮肤的发育和出生后的再生。最近的数据表明，这些生化途径的活性是由表观遗传调控机制控制的。这些机制包括DNA分子的共价修饰和胞嘧啶核苷酸的甲基化/羟甲基化，它们在控制基因激活和抑制方面发挥着重要作用。这个项目将研究被称为Tet1/2/3的调节DNA羟甲基化的酶如何影响正常的生理性皮肤再生，以及当损伤诱导时。该项目还将探索Tet1/2/3如何调节上皮干细胞及其后代(形成皮肤和毛囊上皮)中不同的分子信号，以及它们在伤口愈合中的参与。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。从这项研究中获得的知识也将为开发新的表观遗传疗法提供新的机会，以治愈异常的组织生长和再生条件，如糖尿病患者和老年人的伤口愈合受损。

Biological mechanisms that regulate the development of mammals, including humans, continue during the lifespan of individuals and are altered during ageing. As an organ that covers the body, the skin protects us from a variety of environmental insults, such as mechanical injury, ultraviolet irradiation, and variations in temperature.The skin also provides a unique system for studying the mechanisms that control organ development, regeneration and ageing. Skin development results in formation of the epidermis, a stratified self-renewing epithelium. Additional structures of the skin include hair follicles, nails and glands. After birth, the epidermis continuously regenerates using the ability of epithelial stem cells to supply progeny cells that form all epidermal cell layers. Meanwhile, epidermal regeneration, following skin injury, is controlled by stem cells derived from the hair follicle.Data obtained during the last decade has revealed that many cellular biochemical pathways controlling skin development and its postnatal regeneration are of particular importance. Recent data demonstrate that activity of these biochemical pathways is governed by epigenetic regulatory mechanisms. These mechanisms include covalent modifications of the DNA molecule and methylation/hydroxymethylation of the cytosine nucleotides, which play important roles in the control of gene activation and repression.This project will look at how enzymes called Tet1/2/3 that regulate DNA hydroxymethylation impact normal physiological skin regeneration and when induced by injury. This project will also explore how Tet1/2/3 regulate different molecular signals in epithelial stem cells and their progenies (that form skin and hair follicle epithelium), and their involvement in wound healing.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 also provide new opportunities for the development of novel epigenetic therapies to cure aberrant tissue growth and regenerative conditions, such as impaired wound healing in diabetic patients and in elderly individuals.