UV-induced DNA methyltransferase 1 promotes hypermethylation of tissue inhibitor of metalloproteinase 2 in the human skin.

Background: Ultraviolet (UV) radiation has been reported to influence epigenetic regulation by affecting the expression of genome regulators such as DNA methyltransferase 1 (DNMT1). DNMT1 is a "gene silencer," that is responsible for the maintenance of DNA methylation and contribution to de novo methylation. Implications of DNMT1's involvement in the expression of UV-induced proteins have been previously reported.

Objective: To investigate for changes in DNA methylation-associated gene expressions by UV and to analyze the role of DNA methylation in the suppression of TIMP2 in UV-irradiated human skin.

Methods: The expression of DNA methylation-associated proteins and TIMP2 were analyzed in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. To investigate the relationship between DNMT1 and TIMP2, we assessed the effect of DNMT1 knockdown, inhibition and overexpression on TIMP2 levels in human dermal fibroblasts. Lastly, methylation-specific PCR was used to confirm increased DNA methylation in TIMP2 promoter in response to UV.

Results: DNMT1 expression significantly increased whereas TIMP2 expression decreased in UV-irradiated human skin in vivo and in vitro. Downregulation of DNMT1 by knockdown or inhibition resulted in increased TIMP2 expression, whereas the overexpression of DNMT1 resulted in decreased TIMP2 expression. Lastly, methylation-specific PCR confirmed increased methylation on the CpG island residing in TIMP2 promoter in UV-irradiated human dermal fibroblasts.

Conclusion: These findings suggest that UV-induced expression of DNMT1 may be responsible for mediating DNA hypermethylation in TIMP2, and thus, silencing its expression, in UV-exposed human skin.