Abstract

Zinc deficiency (ZD) first manifests in the skin [1]. ZD leads to fragility and defects in the barrier function of the skin. A human skin equivalent model was generated, to investigate the association between ZD and regulation of acetylation, using 1 mM of TPEN(N,N,N,N-Tetrakis(2-pyridylmethyl)-ethylenediamine), a zinc specific chelator, to mimic ZD. This concentration did not show cytotoxicity (Fig. S1). We found that ZD induced improper stratification with an easily cracked stratum corneum (Fig. 1A).<br /> Zinc supplementation could prevent improper epidermal differentiation by TPEN, indicating that the improper stratification is progressed by ZD, not the side effect of TPEN itself (Fig. 1A). The<br /> border between the stratum granulosum and spinosum appeared ambiguous (Fig. 1A, arrow head) and expression of the terminal differentiation marker filaggrin (FLG) was significantly downregulated in ZD samples (Fig.1B). These results indicated improper differentiation of the epidermis in ZD. Based on our previous report that ZIP10 is the predominantly expressed molecule in the epidermis among the zinc transporter family [2,3], and that histone acetyltransferase (HAT) activity is dependent on cellular zinc level and ZIP10 expression [3], the protein acetylation events in vivo were monitored by immunohistochemistry with an anti？acetylated lysine antibody. The results revealed that ZD decreased Lys-acetylation in the human skin equivalent model (Fig. 1B), implying ZD-caused disturbance in formation of the epidermis by affecting protein acetylation, as observed in the in vitro assessment of keratinocytes [3]. In fact, acetylated proteins were enriched in the basal layer and the outer root sheath of hair follicles in human skin (Fig. 1C), which overlapped with the expression pattern of ZIP10 in skin of human [3] and mouse [2]. In addition, protein acetylation level was apparently decreased in skin of the patient with ZD (Fig.1D), which was similar to that observed in the human skin equivalent model (Fig. 1B).