Epigenetics in Skin Homeostasis and Ageing

Abstract

The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly significant. Epigenetics refers to the regulation of gene expression without altering the underlying DNA sequence. The dynamic nature of the skin, characterized by constant cellular turnover and responsiveness to environmental stimuli, requires precise gene activity control. This control is largely mediated by epigenetic modifications such as DNA methylation, histone modification, and regulation by non-coding RNAs. The present review endeavours to provide a comprehensive exploration and elucidation of the role of epigenetic mechanisms in regulating skin homeostasis and ageing. By integrating our current knowledge of epigenetic modifications with the latest advancements in dermatological research, we can gain a deeper comprehension of the complex regulatory networks that govern skin biology. Understanding these mechanisms also presents promising avenues for therapeutic interventions aimed at improving skin health and mitigating age-related skin conditions.

Keywords: DNA methylation; ageing; epidermis; epigenetics; histone modification; homeostasis; non-coding RNAs; skin.

Figure 1

The epigenetic regulators of skin homeostasis. DNMT1, TETs, UHRF1, JARID2, PRC1 (CBX4), PRC2 (EZH2), GADD45A, KDM6B, miR-30a, miR-148a, and miR-203 control the function of stem cells residing in the basal layer. Specifically, green-coloured factors enhance the proliferative capacity of IFESCs while inhibiting their differentiation. Conversely, red-coloured molecules reduce the proliferative dynamics of IFESCs and promote their differentiation. DNMT1, PRC1, and JARID2 promote the expansion of HFSCs, whereas miR-148a exerts an opposing effect. The apoptosis of keratinocytes is mediated by miR-30a. IFESCs: interfollicular stem cells, HFSCs: hair follicle stem cells, CBX4: chromobox 4, DNMT1: DNA methyltransferase 1, EZH2: enhancer of zeste homolog 2, GADD45A: DNA-damage-inducible protein 45 alpha, JARID2: Jumonji and AT-rich interaction domain containing 2, KDM6B: lysine demethylase 6B, miR-30a: microRNA-30a, miR-148a: microRNA-148a, miR-203: microRNA-203, PRC1: Polycomb repressive complex 1, PRC2: Polycomb repressive complex 2, TETs: ten-eleven translocation family proteins, UHRF1: ubiquitin-like with PHD and ring finger domains 1. Created with BioRender.com.

Figure 2

Epigenetic mediators and marks implicated in aged skin. The effectors of fibroblasts are DNMT1, DNMT3A, DNMT3B, TET2, and several miRNAs. H2A.J, miR-130b, miR-138, miR-181a and miR-181b regulate the biological behaviour of keratinocytes, while H3K9me3, H3K4me3, H3K27me3 and DNMT1 act in epidermal SCs. Upward-pointing arrows indicate elevated levels of the corresponding molecules or marks in aged skin, whereas downward-pointing arrows represent reduced levels. SCs: stem cells, miRNAs: microRNAs, DNMT1: DNA methyltransferase 1, DNMT3A: DNA methyltransferase 3A, DNMT3B: DNA methyltransferase 3B, H2A.J: Histone H2A variant J, H3K27me3: trimethylation of lysine 27 on histone H3, H3K4me3: trimethylation of lysine 4 on histone H3, H3K9me3: trimethylation of lysine 9 on histone H3, TET2: ten-eleven translocation methylcytosine dioxygenase 2. Created with BioRender.com.