Long non-coding RNAs (lncRNAs) constitute an important layer of epigenetic control of gene expression. A few lncRNAs have been uncovered to regulate epidermal differentiation, a critical biological process in barrier maintenance and wound healing. Here, we report a novel skin-specific lncRNA, HOXC13-AS, that regulates keratinocyte differentiation by interacting with COPA (COPI Coat Complex Subunit Alpha) and further modulating endoplasmic reticulum (ER) stress. During human skin wound healing, epidermal cell-specific expression of HOXC13-AS was downregulated in the early phases but recovered to the intact skin level at day 30 after injuries. Moreover, this lncRNA was found significantly upregulated in the psoriatic lesional skin compared to the psoriatic non-lesional skin and the healthy skin. Microarray analysis in keratinocytes with HOXC13-AS knockdown showed that the biological processes associated with epidermis development and keratinocyte differentiation were enriched in the downregulated genes. Functional assays confirmed that loss of HOXC13-AS inhibited the expression of differentiation markers (Keratin10 and Filaggrin) in calcium-treated keratinocytes and reduced the thickness of the organotypic epidermis. Furthermore, RNA pulldown and RNA immunoprecipitation experiments revealed that HOXC13-AS directly interacted with COPA. Silencing of COPA-induced keratinocyte differentiation and ER stress. On the contrary, HOXC13-AS knockdown inhibited ER stress and promoted Golgi redistribution in keratinocytes after Brefeldin A treatment, which effects were also confirmed by HOXC13-AS overexpression. Collectively, we have identified HOXC13-AS as a lncRNA that regulates keratinocyte differentiation through interfering COPI-mediated retrograde transport, and its dysregulation may contribute to the impaired epidermal homeostasis.

ESDR344 - Identification of a novel skin-specific long non-coding RNA regulating keratinocyte differentiation

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING