The epithelial zinc transporter ZIP 10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity

Abstract

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 ZIP10 in the epigenetic maintenance of human epidermal homeostasis. Methods Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10-or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. Results ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 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 ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. Conclusions Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

Epidermal keratinocytes need zinc

“…In their study, in this issue, Bin et al . confirm the physiological significance of zinc regulation in ‘human’ epidermal homeostasis.…”

“…ZIP10 depletion in keratin14‐expressing cells results in epidermal thinning and hair follicle hypoplasia by downregulating p63 activity . In this issue, Bin et al . elucidated the function of ‘human’ ZIP10 that is expressed on undifferentiating KCs of both interfollicular and follicular epidermis and skin appendages.…”

Investigating hair zinc concentrations in children with and without atopic dermatitis

“…[10] The zinc transporter, ZIP10, is also involved in regulation of genes required for epidermal homeostasis and barrier function. [11] Second, low zinc levels may promote cutaneous inflammation. An AD-like eruption can be induced in DS-Nh mice by a zinc-deficient diet.…”

Epigenetic Regulation of Skin Cells in Natural Aging and Premature Aging Diseases

“…p300 (also named EP300, E1A-binding protein p300) and CBP are closely related co-activators that acetylate multiple lysines on histone H3 (K14, K18, and K23) and on histone H4 (K5, K8, and K12). p300 and CBP enzymes play several roles in skin homeostasis: They control cell growth and early differentiation in keratinocytes through the stabilization of p63 and the p53-mediated regulation of p21Waf1/CIP1 expression [108,109], they modulate p16 INK4a expression [110,111], maintain the integrity of skin barrier [112], and regulate the expression of pro-inflammatory and ECM genes in fibroblasts [90,113].…”