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  • To date many studies have reported significant aberrant meth


    To date, many studies have reported significant aberrant methylation patterns in TIMPs in various types of cancer AXL1717 [[16], [17], [18]]. However, little has been reported on the events that lead to the methylation of TIMPs in the UV-irradiated human skin. Therefore, the objective of this study was to investigate for change in the expressions of DNA methylation-associated factors as a response to UV irradiation and to determine which of these components is responsible for inducing DNA methylation, and thus, decreasing TIMP2 expression in the human skin. Our findings revealed significantly increased DNMT1 and MBD1 expressions in acutely UV-irradiated human skin and human dermal fibroblasts. Then, to analyze DNMT1′s inhibitory effect on TIMP2, we observed changed TIMP2 expressions in compliance with the modified DNMT1 expressions. Furthermore, methylation-specific PCR confirmed increased DNA methylation in TIMP2 promoter as a response to UV irradiation. These findings suggest that UV-induced DNMT1 may be responsible for mediating DNA hypermethylation in TIMP2 expressions in the human skin.
    Materials and methods
    Discussion An increase in appreciation for targeted therapy through epigenetic reprogramming has escalated dramatically over the past few decades. Amongst the various mechanisms that exist within the field of epigenetics, DNA methylation has been gaining an enormous amount of interest due to convincing evidences attesting the prevalence of aberrant methylations in cancer cells [[19], [20], [21]]. The majority of these studies, however, pertain to tumor and cancer development, and little is known about the DNA methylation changes that occur in correlation with the molecular pathways of the human skin. UV radiation is a major exogenous toxic agent that induces DNA damage, immunosuppression, ECM degradation, skin cancer and photoaging in the human skin [1,22]. Previously, we demonstrated that the epigenetic modulator, p300 histone acetyltransferase, play a key role in the regulation of UV-induced pathways in vitro and in vivo, such as the activation of MMP-1 transcription and inflammatory cascades [[23], [24], [25]], suggesting that the inhibition of p300 histone acetyltransferase may be a possible therapeutic target for the treatment of photoaging. More recently, we also found that the epigenetic crosstalk between DNA methylation and histone acetylation plays a crucial role in COL1A2 transcription induced by UV irradiation [26]. To be more specific, UV irradiation increased recruitment of DNMT1 to the specific p300 binding site in the COL1A2 promoter and reduced the local recruitment of histone H3 acetylation, p300, and Smad2/3 to the same region of the COL1A2 promoter, which was reversed by a DNA methyltransferase inhibitor (5-AZA-2-dC) [26]. To date, no direct study on the effect of UV on the dynamics of DNA methylation in the human skin was performed. Particularly, although considerable progress has been made to elucidate the pathways involved in the regulation of TIMP2 [7,27], little is known about the events and the mechanisms leading to the DNA methylation of TIMP2 in UV-irradiated human skin. Hence, in this study, we analyzed UV-induced changes in DNA methylation-associated genes and demonstrated its effect on the hypermethylation of TIMP2 promoter by UV irradiation in the human skin. The most crucial process of DNA methylation is executed by DNMTs. In this study, acute UV exposure to the human skin in vivo as well as to the HDFs in vitro increased DNMT1 mRNA and protein, but no significant changes in DNMT3A and DNMT3B expressions were observed (Fig. 1). Similarly, while DNMT1 expression progressively increased following UV irradiation in a time-dependent manner, DNMT3B expression revealed no difference between the control and the UV exposed human skin in vivo (Fig. 1c). The classical methylation model proposes that DNMT1 maintains whereas DNMT3A and DNMT3B establishes de novo methylation patterns [28]. Recent evidence shows that functional redundancy exists among these enzymes, and that DNMT1 and DNMT3B cooperate to maintain DNA methylation [11]. The increase of DNMT1 expression, which was almost absent prior to UV irradiation, may have led to greater cooperation with DNMT3B to produce methylation activity in the skin [11]. On the other hand, DNMT1 alone, without the assistance of de novo methyltransferases, DNMT3A and DNMT3B, can create an extensive degree of global and CpG island methylations [12,[29], [30], [31]]. An analysis of the entire genome-wide methylation activity revealed DNMT1 to possess considerable de novo activity in methylating repetitive and single copy sequences [31].