Award details

Transcriptional control of human epidermal stemness.

Reference	BB/T012978/1
Principal Investigator / Supervisor	Dr Gernot Walko
Co-Investigators / Co-Supervisors
Institution	University of Bath
Department	Biology and Biochemistry
Funding type	Research
Value (£)	536,239
Status	Current
Type	Research Grant
Start date	01/03/2021
End date	29/02/2024
Duration	36 months

Abstract

Trauma, disease or ageing induce tissue damage, which requires the activation of regenerative responses to restore organ function. The skin epidermis is subjected to daily assaults from the external environment. Constant regeneration and repair of human epidermis is endowed by long-lived stem cells (SCs), which generate short-lived, transient-amplifying progenitors that undergo terminal differentiation. How a stable pool of epidermal SCs is maintained during homeostasis and in response to tissue defects remains a fundamental open question. The functionally redundant transcriptional co-activators YAP and TAZ are absolutely essential for sustaining human epidermal SCs. YAP/TAZ are essential for homeostasis and repair not only in the epidermis but also in a variety of other epithelial tissues. However, we have only a rudimentary understanding of the molecular processes involved. In this proposal, we will characterise the molecular mechanisms whereby YAP/TAZ control self-renewal of human epidermal SCs. By mapping the genome-wide binding profiles of YAP/TAZ and their essential co-factor WBP2, as well as of histone modifications defining promoters, enhancers, and super-enhancers using a parallel ChIP-sequencing approach, and by computationally integrating these data with transcriptomics data we will comprehensively define the transcriptional programmes controlled by YAP/TAZ/WBP2 that sustain the SC state in human epidermis. In addition, by using two complementary proteomics approaches we will also obtain a global picture of the transcriptional binding partners of YAP/TAZ that facilitate epidermal SC self-renewal. We will assess their physiological roles in sustaining epidermal stemness in the tissue context using state-of-the-art 3D organotypic human skin models that recapitulate both tissue regeneration and homeostasis. This project will provide new and significant insights into the transcriptional control of human SC self-renewal.

Summary

In everyday life our skin has to cope with a lot of wear and tear. The epidermis forms the surface of the skin and is made up of several layers of cells. The epidermis needs to be renewed constantly to keep our skin in good condition. What's more, trauma, disease or ageing induce tissue damage, so the epidermis needs to be able to repair itself efficiently to keep doing its job - protecting our body from the outside world. Epidermal stem cells make all this possible. They are responsible for constant renewal (regeneration) of our epidermis, and for repairing the epidermis after skin wounding. Epidermal stem cells are one of the few types of stem cells already used to treat patients. They can be taken from a patient, multiplied and used to grow sheets of epidermis in the lab. The new epidermis can then be transplanted back onto the patient as a skin graft to permanently restore massive epidermal defects in patients suffering from severe burn wounds or hereditary skin blistering diseases. Most of the work in the cells of our body - including epidermal stem cells - is done by proteins, which are a huge, varied group of molecules. Therefore, the thousands of genes expressed in a particular cell determine what that cell can do. The instructions for how to make proteins comes from genes. The process by which the information in a gene is turned into a functional protein is called gene expression. Gene expression is a tightly regulated process that allows a cell to respond to its changing environment. Only a fraction of the genes in a cell are expressed at any one time, and differences in gene expression programmes determine the distinct functions of different cell types. The physiological process that maintains a constant number of cells in renewing organs is called tissue homeostasis. How a stable pool of epidermal stem cells is maintained during homeostasis and in response to tissue damage remains a fundamental open question. Two functionally redundant proteins calledYAP and TAZ are absolutely essential for sustaining human epidermal stem cells. YAP/TAZ work in the epidermal stem cell's nucleus where they interact with many other proteins to promote the expression of genes that allow the stem cells to self-renew in order to maintain stem cell numbers during homeostasis and tissue repair. However, we know only very little about which genes are expressed by YAP/TAZ, and which cellular processes these YAP/TAZ-regulated genes control. We also don't know the identity of the various nuclear proteins that interact with YAP/TAZ to help them control gene expression and sustain epidermal stem cells. In this proposal, we will use modern technologies to identify all the genes that are regulated by YAP/TAZ to control epidermal stem cell self-renewal. By using computational tools, we can then categorise these genes into gene expression programmes. In addition, we will also obtain a global picture of the various nuclear proteins that interact with YAP/TAZ to control the gene expression programmes that facilitate epidermal stem cell self-renewal. We will assess the physiological roles of these important YAP/TAZ-associated proteins by using human skin equivalents that we can grow outside of the human body in a culture dish. This project will provide new and significant insights into the control of human epidermal stem cell self-renewal, and enable us to better understand how the epidermis is able to constantly renew itself.

Impact Summary

The main beneficiaries will be the academic community interested in skin biology. New fundamental insights into the transcriptional control mechanisms of epidermal stem cell self-renewal would be of interest especially to those skin biologists with research interests in epidermal tissue homeostasis and repair. In addition, the data from this proposal would be also be of interest to health professionals, due to links to hereditary skin diseases such as Junctional Epidermolysis Bullosa, epidermal cancers and regenerative medicine. Both large and small pharmaceutical industry would be in a position, in collaboration with us, to exploit the intellectual property generated by this proposal. We would envisage that this IP will be associated with novel strategies to sustain epidermal stem cells in culture for prolonged periods, as well as with novel targets for therapeutic interventions into epidermal cancers. Training of the next generation of scientists at both post- and undergraduate levels will be a key aspect of the impact of this project. This research project will result in the training of a highly qualified experimental and computational postdoctoral scientist with skills in an area of biology that is in extremely high demand, as well as of a highly qualified research assistant with extensive expertise in mammalian cell culture and various molecular biology techniques. Undergraduate and Master's students working with us on this project will also receive unique insights into interdisciplinary research at a very early stage, aimed at inspiring them to pursue active careers in research. I would envisage that the data arising from this project would be sufficient for a successful fellowship application of the postdoctoral scientist. The primary way of disseminating the results from our research will be through publications in high quality scientific journals in open access mode, and through presenting our findings to the wider scientific community via oral and poster presentations at national and international scientific conferences. The large-scale datasets generated in this project will be deposited in publicly accessible databases so that they can be of wider benefit to the academic community beyond the duration of this project. It is also important that principle findings of our work will be disseminated to a wider audience. The University of Bath Public Engagement Unit and where appropriate, our Communications team, will help to promote our work through the local, national and international media, responding to requests for information and expertise on a wide range of subjects as well as pro-actively sourcing news and stories arising from research at the University of Bath. Finally, engagement with the general public and policy makers is important to increase accessibility of our research. In addition to continuing our engagement with UK-based skin-focused charities such as the British Skin Foundation and DEBRA, we will play an active role in engaging the public to increase understanding of stem cell research and regenerative medicine. We will do this by participating with interactive displays in local science festivals and by undertaking school visits through the STEMnet Ambassador programme.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Regenerative Biology, Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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