Basic Research & Innovation Division, AmorePacific R&D Unit, Yongin, 17014, Republic of Korea.
Department of Biological Sciences, Ajou University, Suwon, 16499, Republic of Korea.
Br J Dermatol. 2019 Apr;180(4):869-880. doi: 10.1111/bjd.17339. Epub 2018 Dec 5.
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.
In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis.
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.
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.
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.
皮肤是对锌缺乏作出反应而最先发生变化的器官。然而，锌如何参与皮肤的体内平衡，特别是其表观遗传调控的分子机制在很大程度上仍是未知的。
在这项研究中，我们证明了锌水平和锌转运蛋白 ZIP10 在人类表皮体内平衡的表观遗传维持中的重要性。
用抗 ZIP10 抗体对成人皮肤（包括皮肤附属物）进行染色。用 ZIP10 小干扰（si）RNA 或锌螯合剂 TPEN 处理人角质形成细胞后，评估组蛋白乙酰转移酶（HAT）活性。基于角质形成细胞用 ZIP10 siRNA 或 HAT 抑制剂处理的 limma 生物信息学分析，或使用转录因子的公共数据库，分析 ZIP10 或 HAT 调节的基因。使用重建的人类皮肤模型来验证 ZIP10 在表皮分化中的作用以及 ZIP10 与 HAT 之间的功能关联。
ZIP10 主要在毛囊间表皮、表皮附属物和毛囊中表达。ZIP10 耗竭导致重建的人类皮肤模型中的表皮畸形，这是通过下调表观遗传酶 HAT 的活性实现的。这种 HAT 活性的降低，无论是由于 ZIP10 耗竭还是用锌螯合剂 TPEN 处理，都可以通过锌补充来轻易恢复。通过对 SLC39A10（编码 ZIP10）敲低和 HAT 抑制的基因集进行生物信息学分析，我们证明了 ZIP10 和 HATs 与与表皮体内平衡相关的基因的调节密切相关，特别是丝聚合蛋白和金属硫蛋白。
我们的研究表明，ZIP10 介导的锌分布通过 HAT 对表皮体内平衡至关重要。因此，锌依赖性表观遗传调控可以提供替代方案来维持健康的皮肤或缓解具有皮肤屏障缺陷的疾病。
