PRMT5-mediated epigenetic regulation in epithelial development and oncogenesis

During development, the initially single-layered surface ectoderm undergoes precisely coordinated proliferation, differentiation, and adhesion to form the stratified epidermis and oral mucosa. Disruptions in these processes can cause congenital anomalies affecting the epidermis or oral epithelium, while reactivation of these pathways in adults can trigger cutaneous or oral carcinomas. Protein Arginine Methyltransferase 5 (PRMT5)—an enzyme that methylates arginine residues in histone and other proteins—maintains stem-cell quiescence in both development and cancer, leading us to hypothesize that PRMT5 preserves the progenitor status of oral and surface keratinocytes in vivo. To evaluate this hypothesis, we generated conditional knockout (cKO) mice lacking Prmt5 in early ectoderm, impacting the epidermis and oral mucosa. While Prmt5 cKOs displayed severe epidermal defects, compromised barrier function, and reduced postnatal viability, they exhibited no overt oral mucosa defect. Histological analyses revealed significant defects in epidermal stratification, without alterations in apoptosis or proliferation. Single-cell RNA and ATAC-seq analyses identified an atypical population of basal keratinocyte-like cells in Prmt5 cKOs, that exhibited a senescence-like program, characterized by increased expression of Cdkn1a (p21), elevated senescence-associated secretory phenotype (SASP) molecules (Igfbp2), and decreased developmental transcription factor (Trp63) expression. Comparison of these developmentally dysregulated genes with those dysregulated in a Prmt5-deficient oral squamous cell carcinoma (OSCC) cell line revealed significant overlap in molecular programs, including senescence induction. These findings demonstrate that Prmt5 knockout functions through senescence-based pathways in development and cancer, with epidermal loss causing severe epidermal defects in development but potentially serving as a therapeutic target in oral carcinoma.