KLF5 governs sphingolipid metabolism and barrier function of the skin

Stem cells are fundamental units of tissue remodeling, whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward stratifying progenies, skin relies upon its secretory functions to form the outmost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration, whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we establish KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage defining factor across tissue types. Overall design: Skin epithelium of heterozygous (Het) and KLF5 KO E17.5 murine embryos were purified and assayed for their genome-wide transcripts (RNA-Seq). There are three replicates for Het and Klf5 KO RNA-seq respectively. H3K27ac and Klf5 ChIP-Seq were performed on skin epithelium of E17.5 murine embryos and HaCaT cells. ATAC-Seq was performed on the skin epithelium of E17.5 murine embryo.