WTAP-Mediated N6-Methyladenosine of RNAs Facilitate the Pathophysiology of Atopic Dermatitis

Abstract

N6-methyladenosine (m⁶A) is the most abundant dynamic and reversible internal chemical modification of RNA in eukaryotic cells and is essential in multiple pathophysiological processes. However, it has not been reported in atopic dermatitis (AD). We used Arraystar m⁶A-mRNA epitranscriptomic microarray to screen for differentially expressed genes (DEGs) and their m⁶A levels, and m⁶A-related enzymes in patients with AD. We confirmed that the m⁶A RNA methyltransferase Wilms tumor 1-associated protein (WTAP) and two candidate DEGs (S100 calcium-binding protein A9 [S100A9] and serpin peptidase inhibitor, clade B (ovalbumin), member 3 [SERPINB3] were significantly upregulated in keratinocytes in public data and epidermal lesions of patients with AD. In vitro cell experiments confirmed that WTAP influenced the expression of the two candidate DEGs and promoted primary human epidermal keratinocytes (HEKs) proliferation while inhibiting HEKs differentiation. Furthermore, we showed that WTAP, S100A9, and SERPINB3 expression correlated with AD severity. Our findings revealed that WTAP-mediated m⁶A modification promoted the expression of S100A9 and SERPINB3 to aggravate HEK proliferation and dysdifferentiation contributing to the pathophysiological development of AD.