Epigenetic determinants of optimal skin response to UV radiation

这项iCASE博士项目的目的是利用新的表观遗传学技术研究紫外线辐射对皮肤老化的影响。这项研究是与联合利华研发公司合作进行的，皮肤老化的特征是一系列有据可查的生物学变化，包括真皮基质结构的改变(例如，弹性纤维网络的弹性增厚和重塑，胶原蛋白和基质金属蛋白酶基因表达的变化，DNA损伤以及衰老细胞的增加)。然而，人们对这些变化发生并成为老化皮肤稳定特征的确切机制知之甚少。表观遗传学是一个新的令人兴奋的领域，它为衰老生物学提供了新的见解。最近在研究表观遗传变化，特别是DNA甲基化的技术方面的进展，正在进一步了解细胞对生物途径的控制，以及这种控制如何随着年龄的增长而失调。在一定程度上，这是由于DNA甲基化的稳定性质，这意味着，它既是基因活性/表达的决定因素，也是历史环境暴露的良好标志。例如，在来自不同身体部位的皮肤成纤维细胞中发现了发育中的身体图案基因的甲基化差异，这表明这些成纤维细胞对发育过程中的环境暴露有“记忆”。因此，表观遗传学是皮肤衰老研究的一个特别有前途的领域。皮肤细胞对环境应激源(如紫外线辐射)的累积暴露可能通过DNA甲基化水平的变化来反映，DNA甲基化水平影响附近基因的活性。因此，这些差异甲基化区域(DMRS)将精确定位受反复暴露于应激源影响最大的基因。这种表观遗传变化如何影响老化皮肤对新应激源暴露的反应尚不清楚，但可能为恢复皮肤活力或防止损害积累提供新的途径。在英国，大多数人，如果不是几乎所有人，他们的皮肤在夏天将定期暴露在紫外线辐射下。虽然许多研究都集中在单一的高紫外线辐射剂量(即大于最小红斑剂量[MED]的3倍)，但很少有工作专注于多次低剂量暴露，与体内获得的结果相当。事实上，可以说，对于大多数英国人来说，多次低剂量的紫外线辐射暴露比短期的高剂量紫外线辐射更容易导致皮肤老化。因此，我们建议研究多个低剂量的环境应激源(例如，MED的40%-80%的紫外线暴露，典型的正午阳光下20分钟的III型皮肤)对年轻和老年皮肤中人类基因组甲基化水平的影响。因此，这项研究将遵循四个不同的阶段：-确定在体内模拟太阳照射后表观遗传变化的水平。-确定体内表观遗传皮肤对太阳模拟辐射的反应-验证体内蛋白质和/或信使核糖核酸水平的甲基化差异--DMRS与细胞和组织损伤标记物的相关性。

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.