title: Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function.
abstract: A functional epidermal skin barrier requires the formation of a cornified envelope from terminally differentiating keratinocytes. During this process, multiple genetic and environmental signals coordinately regulate protein expression and tissue differentiation. Here we describe a critical role for hypoxia-inducible factors (HIFs) in the regulation of filaggrin expression and skin barrier formation. Similar to other mammalian tissues, fetal epidermis in mice is normally O2 deprived. Simultaneous deletion of Hif1a and Hif2a in murine epidermis revealed defects in keratinocyte terminal differentiation and epidermal barrier formation. Mice lacking Hif1a and Hif2a in the epidermis exhibited dry flaky skin, impaired permeability barrier, and enhanced sensitivity to cutaneous allergens. These defects were correlated with stratum granulosum attenuation and reduced filaggrin expression. Hypoxic treatment of primary keratinocytes induced filaggrin (Flg) gene expression in a HIF1α- and HIF2α-dependent manner, suggesting that one mechanism by which Hif1a and Hif2a loss causes epidermal barrier defects in mice lies in Flg dysregulation. Therefore, low O2 tension is an essential component of the epidermal environment that contributes to skin development and function.
authors.affiliation: Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Waihay J
authors.initials: WJ
authors.lastname: Wong
authors.affiliation: Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA; Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Richardson
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: George
authors.initials: G
authors.lastname: Cotsarelis
authors.affiliation: Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA. Electronic address: celeste2@mail.med.upenn.edu.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism*; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D010539:Permeability; D011401:Promoter Regions, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D000091344:Filaggrin Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007381:Intermediate Filament Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C497443:Hif1a protein, mouse