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. 2020 Apr 30;43(4):323-330.
doi: 10.14348/molcells.2020.0026.

Zinc and Its Transporters in Epigenetics

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Free PMC article

Zinc and Its Transporters in Epigenetics

Sofia Brito et al. Mol Cells. .
Free PMC article

Abstract

Epigenetic events like DNA methylation and histone modification can alter heritable phenotypes. Zinc is required for the activity of various epigenetic enzymes, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone demethylases, which possess several zinc binding sites. Thus, the dysregulation of zinc homeostasis can lead to epigenetic alterations. Zinc homeostasis is regulated by Zinc Transporters (ZnTs), Zrt- and Irt-like proteins (ZIPs), and the zinc storage protein metallothionein (MT). Recent advances revealed that ZIPs modulate epigenetics. ZIP10 deficiency was found to result in reduced HATs, confirming its involvement in histone acetylation for rigid skin barrier formation. ZIP13 deficiency, which is associated with Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS), increases DNMT activity, leading to dysgenesis of dermis via improper gene expressions. However, the precise molecular mechanisms remain to be elucidated. Future molecular studies investigating the involvement of zinc and its transporters in epigenetics are warranted.

Keywords: epigenetics; zinc; zinc transporter.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. The structures of zinc transporters.
(A) Structural model of ZIP. The ZIP protein family is composed of 8 transmembrane domains (TM), with the N- and C-termini facing the extracellular/luminal space. A proline-alanine-leucine (PAL) motif is conserved in each N-terminus, while a cytoplasmic domain (CTD) and a histidine-rich domain is common to TM3 and TM4. Zinc binds to TM4 and TM5 through the HNXXD motif in TM4 and the HEXXH motif in TM5. (B) Structural model of ZnT. The ZnT protein family is composed of 6 TMs. A histidine-rich domain is common to present between TM4 and TM5, with a CTD in the C-terminus. TM2 and TM5 share the zinc binding site through their HXXXD motifs.
Fig. 2
Fig. 2. Epigenetic enzymes possessing zinc-binding sites.
Asterisks denote the zinc-binding sites.
Fig. 3
Fig. 3. Zinc transporters in epigenetic regulations.
The zinc-ZIP10-HAT axis is crucial for the gene expressions for skin integrity like FLG and MT1. The zinc-ZIP13-DNMT axis modulates the LC3 expression for autophagy.

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