Epigenetic determinants of optimal skin response to UV radiation

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The aim of this ICASE PhD project is to investigate the effects of UV radiation on skin ageing, using novel epigenetic techniques. The research is in partnership with Unilever R&D. Ageing skin is characterised by a number of well-documented biological changes including altered architecture of the dermal matrix (e.g. 'elastosis' and remodelling of the elastic fibre network, changes in collagen and matrix metalloproteinase gene expression, DNA damage and an increase in the presence of senescent cells. However, less in known about the exact mechanisms through which these changes occur and become stable features of aged skin.Epigenetics is a new and exciting field that is offering novel insights in the biology of ageing. Recent advances in technologies to study epigenetic changes, particularly DNA methylation, are furthering the understanding of cellular control of biological pathways and how this is dysregulated with increasing age. In part, this is due to the stable nature of DNA methylation which means, as well as a determinant of gene activity/expression, it is a good marker of historic environmental exposures. For example, methylation differences have been found in developmental body patterning genes in skin fibroblasts from different body sites indicating the fibroblasts had a 'memory' of environmental exposures during development. Hence, epigenetics is a particularly promising field for skin ageing research.It is likely that the accumulated exposure of skin cells to environmental stressors (e.g. ultraviolet [UV] radiation) is reflected by variance in DNA methylation levels which influence the activities of nearby genes. These differentially methylated regions (DMRs) will therefore pinpoint the genes most affected by repeated exposure to stressors. How such epigenetic changes influence the response of aged skin to new stressor exposure is unclear, but could offer new routes for rejuvenating the skin or preventing the accumulation of damage.Within the UK, most if not nearly all of the population will have regular UV radiation exposure 'challenges' to their skin during the summer. Although much research has focussed on single high UV radiation doses (i.e. greater than 3 times the minimal erythemal dose [MED]), little work has focussed on multiple low dose exposures, comparable to that attained in vivo. Indeed, it can be argued that for most UK nationals, multiple low dose UV radiation exposures are a greater driver of skin ageing than short very high doses. Hence, we propose to investigate the affects of multiple low doses of an environmental stressor (e.g. UV exposure of 40-80% of the MED, typical of 20 minutes skin type III in the midday sun) on methylation levels across the human genome in young and old skin. The research will therefore follow four distinct phases:- Determining the level of epigenetic change following solar simulated exposures in vivo.- Identifying epigenetic skin response in vivo to solar simulated radiation- Validation of methylation differences at the protein and/or mRNA level in vivo- Correlation of DMRs to makers of cellular and tissue damage.