LncRNA‐WAKMAR2 regulates expression of CLDN1 to affect skin barrier through recruiting c‐Fos

Abstract

Background: Chronic actinic dermatitis (CAD) is an immune-mediated photo-allergic skin disease. In the clinic, the treatment of this disease is hampered by the lack of proper understanding of the skin barrier dysfunction mechanism.Objective: To illuminate the mechanism of skin barrier dysfunction in CAD.Methods: Transcriptome sequencing and protein profiling were used to detect skin barrier injury-related genes. RNA pull down, a promoter-reporter gene assay, and chromatin isolation by RNA purification-sequencing were used to elucidate the effect of WAKMAR2 in skin barrier functionality.Results: Transcriptome sequencing from patient's tissues showed a significantly decreased expression of WAKMAR2. Down-regulation of WAKMAR2 destroyed the keratinocyte barrier. Moreover, WAKMAR2 can directly bind to the c-Fos protein.This novel long non-coding RNA (LncRNA)-protein complexes were targeted to the CLDN1 promotor. Overexpression of WAKMAR2 enhanced the promoter activity of CLDN1, while the addition of AP-1 inhibitor could reverse this phenomenon. Furthermore, our in vivo results suggested that expression of WAKMAR2 was required for the repair of skin damage in mice induced by ultraviolet irradiation. Conclusions:We identified a crucial LncRNA (WAKMAR2) for the protection of the skin barrier in vitro and in vivo. Mechanically, it can specifically interact with c-Fos protein for the regulation of CLDN1, a finding which could be applied for CAD treatment.

m6A modified lncRNA WAKMAR2 induces intestinal inflammation through an allele-specific RNA methylation dependent splicing mechanism

“…Previous studies highlighted the interplay between WAKMAR2 and the p65 subunit of NF-κB, including molecular docking and analysis of p65 phosphorilation, (25,26,29). In addition, NF-κB is a crucial factor in in ammatory processes across multiple cell types, and it has been described to be involved in the induction of in ammation in intestinal epithelial cells (39,40).…”

Successful Treatment of Chronic Actinic Dermatitis with Tofacitinib

“…These effects can be attributed to the destruction of the skin barrier, exudation, and desquamation of the skin. 3 At the genetic level, the expression of the WAKMAR2 gene might be associated with the dermatological barrier in CAD, 32 whereas UV-induced hsa-miR-31-3p has been correlated with the severity of CAD, and plays a significant role in regulating the keratinocyte permeability barrier by targeting CLDN1, a gene involved in regulating epithelial barrier permeability and barrier function. 8 Tofacitinib appears to be a promising therapeutic option for patients with sun-induced pruritic plaques that do not respond adequately to conventional treatment.…”