m 6 A ‐Mediated Regulation of p63 by the METTL16 ‐ IGF2BP2 Axis Governs Epithelial Stem Cell Function and Epidermal Development

ABSTRACT The transcription factor p63 is indispensable for epithelial stem cell proliferation/differentiation and epidermal development, with alterations in the p63 pathway underlying a subset of ectodermal dysplasias. Despite its critical role, the mechanisms regulating p63 expression remain poorly understood. Here, we identify an m 6 A‐mediated posttranscriptional mechanism controlling the expression of ΔNp63 , the predominant functional p63 isoform in epidermal basal cells. We found that Cre‐mediated conditional deletion of Mettl16 , encoding a conserved m 6 A methyltransferase, in mouse epithelial basal cells caused severe skin developmental abnormalities, reminiscent of human ectodermal dysplasias. RNA sequencing revealed significant downregulation of ΔNp63 and its target genes in Mettl16‐ deficient skin, which linked METTL16 to p63 pathways. Mechanistically, we demonstrated that METTL16 directly binds to ΔNp63 mRNA to mediate its m 6 A modification; this modified ΔNp63 mRNA is subsequently recognized by the m 6 A reader IGF2BP2, which stabilizes ΔNp63 mRNA and thereby modulates its protein levels. Critically, restoration of ΔNp63 expression mitigated the epidermal defects in Mettl16 ‐deficient mice. Collectively, our findings uncover a novel METTL16‐m 6 A‐IGF2BP2‐ ΔNp63 regulatory axis governing epidermal development, providing insights into the etiology of ectodermal dysplasias.