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

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.

Epigenetic mechanisms play important roles in the control of stem cell (SCs) activity during development and regeneration, however understanding of how these mechanisms become altered as a result of disorders (cancer, impaired wound healing, etc.) is increasingly seen as a priority in biomedical research.
The Polycomb group proteins are transcriptional repressors playing critically important roles in the control of stem cell activity and their differentiation into specialized cell types. By interacting with each other and forming multi-protein complexes, they mediate histone modifications leading to chromatin compaction and gene silencing.
Here, we will test a hypothesis that Polycomb group gene Cbx4 is a critical determinant that controls maintenance of epithelial identity and the proliferative activity of the skin epithelial SCs during physiological and injury-induced skin regeneration via two Specific Aims:
1. Define the role for Cbx4 in the maintenance of proliferative activity, epithelial identity and differentiation of skin epithelial SCs during hair cycle-associated skin regeneration.
2. Identify the role of Cbx4 in balancing between epidermal commitment and epithelial-mesenhymal transition in epithelial SCs during wound healing.
To address these aims, we will generate genetically modified mice with the deletion of Cbx4 in K14+ and K15+ skin epithelial SCs. In addition to mice, we will use ex vivo human skin wound and 3D organotypic models to assess the role of Cbx4 in human skin maintenance and regeneration. Together, this study will allow us to comprehensively analyse the consequences of Cbx4 loss in skin SCs for normal physiological and injury-induced regeneration.
This project will provide new important insights into fundamental mechanisms that regulate SC activity inside and outside of the skin, and will serve as an important platform for the development of new epigenetic drugs to target stem cells for the needs of regenerative medicine.

An understanding of the biological mechanisms regulating stem cell activity is highly important for a better understanding of the changes that occur during life, and effects this may have on health status and longevity of individuals. This project will look at how Cbx4, an epigenetic regulator that controls gene expression via modification of histones and other proteins, impacts on stem cell activity during skin regeneration, wound healing and ageing.
While the immediate benefits of this knowledge will be related to scientific community, this project will have long-term benefits to the UK economy and to public health and well-being through significant impact on the pharmaceutical industry, healthcare professionals and their patients, and the general public interested in modern science.
SCIENTIFIC COMMUNITY
Delineating the functions of the Cbx4 gene in the control of stem cells during skin regeneration and wound healing will advance knowledge for researches working in the areas of developmental biology, molecular biology, stem cell biology and tissue regeneration, as well as clinical and veterinary medicine.
PUBLIC HEALTH & AWARENESS
This project will have significant health implications and will benefit the public sector, including health professionals and their patients. Chronic wounds represent a substantial public health problem; in the UK, chronic wounds affect approximately 200,000 patients, with an estimated 3% of the annual healthcare budget spent on chronic wound care alone. The information generated by this project will provide new opportunities for therapeutic interventions to cure chronic epithelial wounds and will also influence the generation of new therapeutics for specific forms of hair loss. This will ultimately contribute to the enhancement of quality of life.
INDUSTRY
Business/industry will benefit from this project by expanding the understanding of molecular mechanisms that control skin and hair regeneration. This is vital for the development of new approaches to improve diagnosis and treatment of skin and hair disorders, leading to substantial economical benefits in relation to the life science industries. Knowledge transfer activities with industrial partners will be actively implemented for those areas of the results that can be used for new therapeutic product development and the research will lead to the development of research-led teaching activities in the relevant higher education courses for basic scientists and health professionals - thus educating future generations.
To ensure that the results of the proposed project will be made available to the general public and to the specific groups mentioned above, several approaches will be pursued. The results will be presented at prestigious international conferences. Furthermore since 2012, the Centre for Skin Sciences biannually hosts the International Symposium "Epigenetic Control of Skin Development and Regeneration" (2016) with a focus on more translational approaches and development of novel epigenetic therapies for the needs of regenerative medicine and stem cell-based therapy. This symposium represents a unique opportunity by bringing skin biologists together with scientists studying epigenetic regulatory mechanisms and industry to provide a platform for establishing intradisciplinary collaboration. Our data will be published in international peer-reviewed journals with the widest possible audience. Information on the project outcomes will also be made available to relevant Health and Wound-healing charities.