The skin-specific long non-coding RNA TEDAR orchestrates late epidermal differentiation via an ERK-KLF4 cytoplasmic regulatory axis

Abstract The formation of a functional skin barrier depends on terminal keratinocyte differentiation, yet the contribution of long non-coding RNAs to this process remains incompletely understood. Here, using transcriptome analysis of more than 15,000 RNA-seq samples across 54 human tissues, we identify TEDAR (Terminal Epidermal Differentiation-Associated RNA), a highly skin-enriched lncRNA. Single-molecule RNA in situ hybridization revealed that TEDAR is confined to the uppermost granular layer of the epidermis, representing an exceptionally spatially restricted expression pattern. Functional studies demonstrated that CRISPR-mediated activation of TEDAR promotes keratinocyte differentiation even in the absence of external cues, while its depletion impaired late epidermal differentiation. In three-dimensional skin equivalents, TEDAR depletion severely compromises stratum corneum formation, highlighting its importance for proper epidermal barrier assembly. Mechanistically, TEDAR associates with ERK1/2-containing complexes and restrains ERK phosphorylation, thereby facilitating the nuclear accumulation of KLF4, a key regulator of epidermal differentiation. KLF4 depletion attenuated TEDAR-induced expression of several late differentiation genes, supporting a functional TEDAR–ERK–KLF4 axis. Clinically, TEDAR expression was reduced in cutaneous squamous cell carcinoma (cSCC) and chronic inflammatory skin diseases, including psoriasis and atopic dermatitis. Moreover, IL-22 suppressed TEDAR via STAT3 signalling in epidermal models. These findings identify TEDAR as an important regulator of terminal epidermal differentiation and suggest that its suppression may contribute to disturbed differentiation in inflammatory and neoplastic skin diseases.