UV-induced DNA methylation changes in the epidermis reveal genes that may be involved in an age-independent UV response

Ultraviolet radiation (UVR) from sunlight affects the epigenome of the epidermis, but the associated biological mechanisms are unknown. The aim of this work was to explore how DNA methylation (DNAm) may mediate the skin response to UVR. Previously collected epidermal DNAm data revealed that following sub-erythemal UV exposure, significant differential DNAm occurs in aged skin (>65y) (adjusted (adj) p value (p)<0.05), but not in young skin (18-30y). Seventeen DNAm sites from the dataset were differentially methylated (adj p<0.20) in both aged and young skin following UV exposure, and hence may be involved in an age-independent UV response. The genomic context of these sites was determined, with twelve of the DNAm sites residing in thirteen genes. Following a literature search of the associated genes, only KITLG was found to have a known role in the UV response. Therefore, significantly enriched pathways (p<0.05) relating to the genes were identified with the DAVID functional annotation tool. The most significantly associated GO term category was calcium ion regulation (n=2 genes; p=0.008), a noteworthy result given that UVR causes a rapid increase in Ca2+ levels. Followed by this was development (n=7; p=0.015), and immune function (n=3; p=0.021). The top BioGRID interactions were with VIRMA (n=6; p=0.001) and PFN1 (n=3; p=0.006). VIRMA is required for m6A methylation of mRNA, a modification which is rapidly induced at sites of UV-induced DNA damage, and PFN1regulates the DNA repair response in keratinocytes post-UV exposure. Binding sites for AP1, a regulator of UV-induced inflammatory gene expression, were also found within eight genes (p=0.035). Furthermore, systemic lupus erythematosus, an autoimmune disease with symptoms including sun-sensitivity, was linked to two genes. These results reveal possible biological pathways mediating the UV response in skin. Future work to validate this will include quantitative-PCR and immunostaining.