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

Polycomb组基因Cbx4在控制皮肤再生和伤口愈合中的作用

• 批准号: MR/N009630/1
• 负责人: Andrei Mardaryev
• 金额: $ 69.44万
• 依托单位: University of Bradford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN009630%2F1
• 关键词: Role; Polycomb; group; gene; Cbx4

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.

皮肤是覆盖身体的器官，保护我们免受各种环境的伤害，如机械损伤，微生物入侵，紫外线照射，并防止水分流失。为了实现这样的重要功能，皮肤必须在人的一生中不断地自我再生，并且皮肤的这种自我再生能力依赖于存在于表皮和毛囊（皮肤的主要上皮结构）中的上皮干细胞的正常功能。这些干细胞是长寿命细胞，同时产生短寿命的特化后代，形成所有保护性表皮细胞层和毛发。随着皮肤老化，干细胞的功能活动下降，导致表皮变薄和脱发，以及降低它们在损伤后再生皮肤的能力。在过去十年中获得的数据显示，有多种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控机制。其中一个表观遗传学机制是Polycomb组蛋白修饰组蛋白（与DNA密切相互作用的蛋白质），从而抑制基因的表达，从而改变许多重要的细胞功能。本项目将研究Polycomb组基因Cbx4如何抑制许多基因，影响正常的生理和损伤诱导的再生。我们还将探索Cbx4如何调节上皮干细胞及其后代（形成表皮和毛发的细胞）中的不同分子信号，以及它们如何参与伤口愈合。此外，我们还将研究Cbx4如何控制皮肤干细胞的长期存活以及它们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，将有助于了解控制其他上皮组织（如肠、牙齿、肾脏和肺的上皮细胞）发育和再生的机制。因此，从这项研究中获得的知识将提供新的机会，以帮助开发新的表观遗传疗法，旨在防止异常组织生长和再生限制，如糖尿病患者和老年人的伤口愈合受损。

项目成果

Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium.

• DOI: 10.1083/jcb.201506065
• 发表时间: 2016-01-04
• 期刊: The Journal of cell biology
• 作者: Mardaryev AN;Liu B;Rapisarda V;Poterlowicz K;Malashchuk I;Rudolf J;Sharov AA;Jahoda CA;Fessing MY;Benitah SA;Xu GL;Botchkarev VA
• 通讯作者: Botchkarev VA

5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells.

• DOI: 10.1371/journal.pgen.1006966
• 发表时间: 2017-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Poterlowicz K;Yarker JL;Malashchuk I;Lajoie BR;Mardaryev AN;Gdula MR;Sharov AA;Kohwi-Shigematsu T;Botchkarev VA;Fessing MY
• 通讯作者: Fessing MY

Exploring a Role for Regulatory miRNAs In Wound Healing during Ageing:Involvement of miR-200c in wound repair.

• DOI: 10.1038/s41598-017-03331-6
• 发表时间: 2017-06-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Aunin E;Broadley D;Ahmed MI;Mardaryev AN;Botchkareva NV
• 通讯作者: Botchkareva NV