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The epithelial zinc transporter ZIP 10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity
Author(s) -
Bin B.H.,
Lee S.H.,
Bhin J.,
Irié T.,
Kim S.,
Seo J.,
Mishima K.,
Lee T.R.,
Hwang D.,
Fukada T.,
Cho E.G.
Publication year - 2019
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.17339
Subject(s) - human skin , biology , epigenetics , microbiology and biotechnology , homeostasis , epidermis (zoology) , downregulation and upregulation , gene knockdown , biochemistry , genetics , gene , anatomy
Summary Background The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. Objectives In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP 10 in the epigenetic maintenance of human epidermal homeostasis. Methods Adult human skin, including skin appendages, were stained with anti‐ ZIP 10 antibody. Histone acetyltransferase ( HAT ) activity was assessed after treating human keratinocytes with ZIP 10 small interfering (si) RNA s or the zinc chelator TPEN . ZIP 10‐ or HAT ‐regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP 10 si RNA s or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP 10 in epidermal differentiation and the functional association between ZIP 10 and HAT . Results ZIP 10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP 10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT . This decreased HAT activity, resulting from either ZIP 10 depletion or treatment with the zinc chelator TPEN , was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC 39A10 (encoding ZIP 10) and HAT inhibition, we demonstrated that ZIP 10 and HAT s were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. Conclusions Our study suggests that ZIP 10‐mediated zinc distribution is crucial for epidermal homeostasis via HAT s. Therefore, zinc‐dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.