Skin wound healing triggers epigenetic modifications of histone H4

Abstract

Background: The skin is the largest organ of the human body. Upon injury, the skin triggers a sequence of signaling pathways that induce epithelial proliferation, migration, and ultimately, the re-establishment of the epithelial barrier. Our study explores the unknown epigenetic regulations of wound healing from a histone perspective. Posttranslational modifications of histones enhance chromatin accessibility and modify gene transcription. Methods: Full-thickness wounds were made in the dorsal skin of twenty-four C57/B6 mice (C57BL/6J), followed by the use of ring-shaped silicone splints to prevent wound contraction. Tissue samples were collected at three time points (post-operatory day 1, 4, and 9), and processed for histology. Immunofluorescence was performed in all-time points using markers for histone H4 acetylation at lysines K5, K8, K12, and K16. Results: We found well-defined histone modifications associated with the stages of healing. Most exciting, we showed that the epidermis located at a distance from the wound demonstrated changes in histone acetylation, particularly the deacetylation of histone H4K5, H4K8, and H4K16, and hyperacetylation of H4K12. The epidermis adjacent to the wound revealed the deacetylation of H4K5 and H4K8 and hyperacetylation of H4K12. Conversely, the migratory epithelium (epithelial tongue) displayed significant acetylation of H4K5 and H4K12. The H4K5 and H4K8 were decreased in the newly formed epidermis, which continued to display high levels of H4K12 and H4K16. Conclusions: This study profiles the changes in histone H4 acetylation in response to injury. In addition to the epigenetic changes found in the healing tissue, these changes also took place in tissues adjacent and distant to the wound. Furthermore, not only deacetylation but also hyperacetylation occurred during tissue repair and regeneration.

The epigenetics of keloids

“…45,46 Injury to skin tissue also alters histone H4 lysine residue acetylation status at different stages in wound healing, with a coordinated pattern of both hyper-and deacetylation in distant and adjacent skin, migrating epithelium and newly formed epidermis. 47 Global hypermethylation of DNA mediated by the upregulation of DNA methyltransferases is also observed during re-epithelialisation. 48,49 There are also epigenetic modulations regulating dermal repair, although these are less well-characterised.…”

TIP60 acts as a regulator of genes involved in filopodia formation and cell migration during wound healing

“…Our findings corroborate with other studies which showed enhanced acetylation of histone H4 post-wound induction. According to latest research findings by Nascimento-Filho CHV et al., it has been shown that histone modification pattern alters during different stages of healing and may also vary depending on the state and location of the surrounding cells from the injured area ( 55 ). Further they observed that, migrating epithelial cells showed remarkably enhanced H4K12 hyperacetylation in early stages of wound healing, while histone H4K16 was the only lysine found to be hyperacetylated in the epithelial cells of closed wound areas.…”

Epigenetic Regulation of Epidermal Differentiation

“…It was also found that the activation of histone acetyltransferases or inhibition of deacetylases promoted wound closure [ 76 ]. Accordingly, changes in the acetylation status of histone H4 lysine residues were observed at the wound margin in mice [ 77 ].…”