Epigenetic and metabolic regulation of epidermal homeostasis

Abstract

Continuous exposure of the skin to environmental, mechanical and chemical stress necessitates constant self-renewal of the epidermis to maintain its barrier function. This self-renewal ability is attributed to epidermal stem cells (EPSCs), which are long-lived, multipotent cells located in the basal layer of the epidermis. Epidermal homeostasis - coordinated proliferation and differentiation of EPSCs - relies on fine-tuned adaptations in gene expression which in turn are tightly associated with specific epigenetic signatures and metabolic requirements. In this review, we will briefly summarize basic concepts of EPSC biology and epigenetic regulation with relevance to epidermal homeostasis. We will highlight the intricate interplay between mitochondrial energy metabolism and epigenetic events - including miRNA-mediated mechanisms - and discuss how the loss of epigenetic regulation and epidermal homeostasis manifests in skin disease. Discussion of inherited epidermolysis bullosa (EB) and disorders of cornification will focus on evidence for epigenetic deregulation and failure in epidermal homeostasis, including stem cell exhaustion and signs of premature ageing. We reason that the epigenetic and metabolic component of epidermal homeostasis is significant and warrants close attention. Charting epigenetic and metabolic complexities also represents an important step in the development of future systemic interventions aimed at restoring epidermal homeostasis and ameliorating disease burden in severe skin conditions.

Keywords: epidermal stem cells; epidermolysis bullosa; epigenetics; keratinocytes; miRNAs; mitochondria.

FIGURE 1

Epigenetic effectors and epidermal homeostasis. Maintenance and differentiation of EPSCs critically governs epidermal homeostasis. Individual, proliferating EPSCs (indicated as shaded cells) are located in the basal layer. As cells differentiate, they progressively move upward through the various layers of the epidermis. Eventually, these cells lose their nuclei before forming the layers of the outermost stratum corneum. Multiple epigenetic effectors regulate EPSC self‐renewal, proliferation and differentiation. These factors control DNA methylation (indicated in blue), histone modification and chromatin remodelling (indicated in orange). Abbreviations: BL, basal layer; BM, basement membrane; DNMT, DNA methyltransferase; EPSC, epidermal stem cell; HDAC, histone deacetylases; PRC, polycomb repressive complex; SC, stratum corneum; SG, stratum granulosum; SL, stratum lucidum; SS, stratum spinosum; TET, ten‐eleven translocation; TrxG, trithorax group proteins

FIGURE 2

Proliferation potential of primary keratinocytes from EB patients. Keratinocytes from a 49‐year‐old JEB patient were transfected to re‐express LAMB3 protein. Upper panel: LAMB3‐deficient patient keratinocytes in cell culture. After transfection, there is improved clonal potency as can be seen by the increased number and size of red‐stained clones in the lower panel (M. De Luca et al, unpublished results). CFE: Colony‐forming units