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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282439 | GEO | 2025/04/13

REPOSITORIES: GEO

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Project description:Hair follicle formation depends on reciprocal epidermal-dermal interactions and occurs during skin development, but not in adult life. This suggests that the properties of dermal fibroblasts change during postnatal development. To examine this, we used a PdgfraEGFP mouse line to isolate GFP-positive fibroblasts from neonatal skin, adult telogen and anagen skin and adult skin in which ectopic hair follicles had been induced (EF skin) by transgenic epidermal activation of beta-catenin. We also isolated epidermal cells from each mouse. The gene expression profile of EF epidermis was most similar to that of anagen epidermis, consistent with activation of beta-catenin signalling. In contrast, adult dermis with ectopic hair follicles more closely resembled neonatal dermis than adult telogen or anagen dermis. In particular, genes associated with mitosis were upregulated and extracellular matrix-associated genes were downregulated in neonatal and EF fibroblasts. We confirmed that sustained epidermal beta-catenin activation stimulated fibroblasts to proliferate to reach the high cell density of neonatal skin. In addition, the extracellular matrix was comprehensively remodelled, with mature collagen being replaced by collagen subtypes normally present only in developing skin. The changes in proliferation and extracellular matrix composition originated from a specific subpopulation of fibroblasts located beneath the sebaceous gland. Our results show that adult dermis is an unexpectedly plastic tissue that can be reprogrammed to acquire the molecular, cellular and structural characteristics of neonatal dermis in response to cues from the overlying epidermis. We have isolated the following populations of cells from mouse back skin by flow cytometry: 1A) GFP+ WT neonatal dermal fibroblasts, 1B) ItgA6+ WT neonatal epidermal keratinocytes, 2A) GFP+ WT telogen dermal fibroblasts, 2B) ItgA6+ WT telogen epidermal keratinocytes, 3A) GFP+ D2 transient activation (anagen) dermal fibroblasts, 3B) ItgA6+ D2 transient activation (anagen) epidermal keratinocytes, 4A) GFP+ D2 sustained activation (ectopic follicles) dermal fibroblasts, 4B) ItgA6+ D2 sustained activation (ectopic follicles) epidermal keratinocytes

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

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