506 Epidermal epitranscriptomics: METTL3 dependent m6A maintains the epidermal stem cell state through regulation of chromatin-modifying enzymes

The balance between epidermal stemness and differentiation requires regulated spatiotemporal changes regulation of gene expression. One emerging area is that epitranscriptomics (regulated RNA modifications), which offers an additional layer in a spatiotemporal- signal-dependent manner. However, its significance healthy diseased epidermis poorly understood. N6-methyladenosine (m6A) the most abundant internal mRNA modification eukaryotes found to facilitate rapid transcriptome turnover during cell maintain homeostasis. Its deposition on nascent pre-mRNA carried out by multicomponent writer complex consists catalytic subunit METTL3. To understand role METTL3 epidermis, we created mice with epidermis-specific knockout Mettl3 (Krt14-Cre; fl/fl). These displayed dramatic epithelial phenotype marked absence hair, altered dynamics, as well oral epithelium was notable for lack filiform papillae ulcerations. Consistent these changes, transcriptional profiling RNA-seq demonstrated loss expression stem basement membrane genes along concomitant upregulation keratinocyte genes. Mechanistically, our results suggest m6A exerts effects through ability directly regulate various chromatin-modifying enzymes. Collectively, demonstrate broad regulatory epitranscriptome can play biology underscore importance further studies examining tissue regeneration carcinogenesis.