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This self\u2010renewal ability is attributed to epidermal stem cells (EPSCs), which are long\u2010lived, multipotent cells located in the basal layer of the epidermis. Epidermal homeostasis \u2013 coordinated proliferation and differentiation of EPSCs \u2013 relies on fine\u2010tuned 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 \u2013 including miRNA\u2010mediated mechanisms \u2013 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.<\/jats:p>","DOI":"10.1111\/exd.14305","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T09:55:12Z","timestamp":1613642112000},"page":"1009-1022","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Epigenetic and metabolic regulation of epidermal homeostasis"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5354-240X","authenticated-orcid":false,"given":"Roland N.","family":"Wagner","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefina","family":"Pi\u00f1\u00f3n Hofbauer","sequence":"additional","affiliation":[{"name":"EB House Austria Research Program for Molecular Therapy of Genodermatoses Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Wally","sequence":"additional","affiliation":[{"name":"EB House Austria Research Program for Molecular Therapy of Genodermatoses Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kofler","sequence":"additional","affiliation":[{"name":"Research Program for Receptor Biochemistry and Tumor Metabolism Department of Pediatrics University Hospital of the Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-1334","authenticated-orcid":false,"given":"Matthias","family":"Schmuth","sequence":"additional","affiliation":[{"name":"Department of Dermatology Medical University Innsbruck Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Holostem Terapie Avanzate S.r.l. 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