DNA methylation contributes to the site-specific regulation of HOXA cluster gene expression

The skin is the largest organ covering the entire body, composed of three layers: the epidermis, dermis, and subcutaneous tissue. While the thickness and elasticity of the skin are known to vary depending on the body site, the mechanisms underlying these differences remain unclear. Recent studies have reported that HOX genes, which determine positional identity during development, are also expressed and functional in adult tissues. We found that the expression of HOXA cluster genes in dermal fibroblasts derived from adult skin is regulated in a site-specific manner. Inhibition of HOXA9 expression in adult dermal fibroblasts resulted in decreased cell proliferation and downregulation of extracellular matrix-related genes. These results suggest that the HOX genes function as factors that produce site-specific differences in skin properties. To verify how site-specific expression of HOXA genes is regulated, methylation analysis was performed. The results showed that methylation level around the HOXA9 gene was higher in cells derived from the face than those from the abdomen and buttocks. This result suggests that region-specific expression during development is preserved in adult skin and is responsible for the regional differences in skin properties. To elucidate the regulatory mechanisms of site-specific HOXA gene expression, methylation arrays were performed using human dermal fibroblasts derived from the face, abdomen, and buttocks.