UV irradiation‐induced DNA hypomethylation around WNT1 gene: Implications for solar lentigines

Abstract

Wnt/β‐catenin signalling promotes melanogenesis in melanocytes and also induces melanocytogenesis from melanocyte stem cells (McSCs). Previous study reported that WNT1, a ligand which activates Wnt/β‐catenin signalling pathway, was more highly expressed in the epidermis at SLs than in normal skin areas, suggesting that WNT1 causes hyperpigmentation. To elucidate the mechanism by which WNT1 expression is increased in SLs, we examined the methylation of 5‐carbon of cytosine (5mC), that is 5‐methylcytosine (5mC) level, in a region within the WNT1 promoter; the methylation of the region was known to negatively regulate WNT1 gene expression. We used an immortalized cell line of human interfollicular epidermal stem cells to analyse the effect of UVB irradiation on DNA methylation level of WNT1 promoter and found that UVB irradiation caused demethylation of WNT1 promoter and promoted WNT1 mRNA expression. It was also found that UVB irradiation reduced the expression of DNA methyltransferase 1 (DNMT1), an enzyme responsible for maintaining methylation patterns during cell division. Pathological analysis of SLs and non‐SL regions in the human skin revealed that both DNMT1 expression and 5mC level were decreased at SLs compared to non‐SL skins. Furthermore, bisulphite sequencing showed that the methylated CpG level in WNT1 promoter was also lower at SLs than in non‐SL skins. Thus, in the skin exposed to a high amount of UV rays, excessive expression of WNT1 is thought to be caused by the demethylation of WNT1 promoter, and the upregulated WNT1 promotes melanocytogenesis and melanogenesis, then resulting in SL formation.

Focus Theme Issue: “Vitiligo and other pigmentary disorders”

“…Two papers concerning the increasingly important topic of epigenetics of pigmentation are also featured: Takaaki Yamada and colleagues, from Fujita Health University, Toyoake, Japan, suggest that, in skin exposed to a high amount of UV irradiation, demethylation of the WNT1 promoter induces melanocytogenesis and melanogenesis resulting in the formation of solar lentigines . This study adds a potential new pathomechanism to the study of age spots .…”

How to design robust assays for human skin pigmentation: A “Tortoise and Hare challenge”

“…There is, I believe, a considerable clinical unmet need in this area, as both hypopigmentary and hyperpigmentary disorders (eg vitiligo, 16–18 melasma, 19–21 solar lentigines 22 etc.) exert significant clinical and personal burdens 23,24 .…”

Skin epigenetics

“…35 In addition, solar lentigines have been linked to UV-induced DNA hyopmethylation in the WNT1 gene. 36 studied in melanoma where DNA methylation changes have been linked to tumorigenesis and metastasis. 38…”