Epigenetic determinants of optimal skin response to UV radiation

Abstract

Genome-wide changes in DNA methylation (DNAm) are thought to contribute to ageing phenotypes by alteration of gene expression and genomic stability. The skin, by virtue of its direct exposure to the environment, also ages via extrinsic factors such as ultraviolet radiation (UVR). Chronically UVR exposed skin has been shown to harbour its own pattern of aberrant DNAm pattern. However, the interaction of the intrinsically-aged DNA methylome and the ability of the skin to respond optimally to UVR exposure has not thus far been delineated. DNA methyltransferases (DNMTs) orchestrate the establishment and maintenance of DNAm, together with the ten-eleven-translocation (TET) proteins that facilitate its removal by oxidation. This study showed that the expression of DNMTs decreases upon traversing through the terminally differentiated layers of the epidermis, whereas the TETs appear inversely upregulated. This suggests that DNAm and the enzymes that control it are fundamentally important to epidermal homeostasis. To investigate the contribution of DNAm to the pathogenesis of photodamage, sub-erythemal doses of UVR were applied to young and aged skin to recapitulate the early DNAm changes in chronically photoexposed skin. Substantial losses of DNAm in the aged but not young epidermis were observed. Aged epidermis also showed a dampened transcriptional response following UVR challenge, characterised by failure to activate key UVR-responsive pathways. Finally, this study investigated the differences in DNAm due to intrinsic ageing. Changes in DNAm were significantly correlated with the expression of 651 genes, enriched in pathways related to: metabolism, pluripotency of stem cells and cancer. Additionally, a significant proportion of the genes showing a dampened response in aged epidermis following UVR challenge were those found to be differentially methylated between the young and aged epidermis prior to UVR challenge. This suggests that DNAm changes that occur in the skin with increasing age impair phenotypic plasticity, disposing the skin to respond poorly to UVR exposure.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Christopher Griffiths (Supervisor) & Rachel Watson (Supervisor)