Disrupted epigenetic regulation in human senile lentigines revealed by characterizing gene expression and DNA methylation alterations

Senile lentigines (SL) are common hyperpigmented lesions. While previous studies have characterized morphological changes and gene expression profiles in SLs, the relationship between epigenetic regulation and these transcriptional alterations has not been thoroughly investigated. In this study, we aimed to characterize the transcriptional and epigenetic profiles of SLs by integrating RNA sequencing (RNA-seq) and whole-genome bisulfite sequencing (WGBS). Our gene expression profiling revealed 139 upregulated and 56 downregulated genes, with key pathways related to “collagen formation” and “mitochondrial respiratory chain complex assembly.” DNA methylation analysis detected 1,580 hypermethylated and 2,708 hypomethylated differentially methylated promoter regions (DMRs). Consistent with the “information theory of aging”, we found a global disruption of tight epigenetic regulation in SLs, with methylation states of promoter-proximal regions drifting from extreme (0% or 100%) toward intermediate levels. Furthermore, we specifically focused on an inflammatory gene IL-6R, which was hypomethylated at promoter-associated DMRs and upregulated at the RNA level in SLs; immunostaining confirmed increased IL-6R protein, supporting a correlation between IL-6R hypomethylation and protein expression and suggesting that SLs exhibit a chronic inflammatory condition. To our knowledge, this study provides the first evidence that SLs are characterized by a widespread disruption of promoter-proximal epigenetic regulation. Our findings suggest that the disruption of epigenetic information contributes to the formation of SLs and points to the possibility that these disrupted states might be repairable through epigenetic reprogramming.