The long non‐coding RNA LINC00941 and SPRR5 are novel regulators of human epidermal homeostasis

Several long non‐coding RNAs (lncRNAs) act as regulators of cellular homeostasis; however, few of these molecules were functionally characterized in a mature human tissue environment. Here, we report that the lncRNA LINC00941 is a crucial regulator of human epidermal homeostasis. LINC00941 is enriched in progenitor keratinocytes and acts as a repressor of keratinocyte differentiation. Furthermore, LINC00941 represses SPRR5, a previously uncharacterized molecule, which functions as an essential positive regulator of keratinocyte differentiation. Interestingly, 54.8% of genes repressed in SPRR5‐deficient epidermal tissue are induced in LINC00941‐depleted organotypic epidermis, suggesting a common mode of action for both molecules. Synopsis lncRNA LINC00941 inhibits premature differentiation in weakly differentiated strata of the human epidermis through repression of previously uncharacterized SPRR5, shown here to promote keratinocyte differentiation. The lncRNA LINC00941 regulates human epidermal homeostasis. SPRR5 functions as an essential positive regulator of keratinocyte differentiation. LINC00941 and SPRR5 conversely regulate a common set of target genes. Graphical Abstract lncRNA LINC00941 inhibits premature differentiation in weakly differentiated strata of the human epidermis through repression of previously uncharacterized SPRR5, shown here to promote keratinocyte differentiation.