METTL1-mediated m7G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis.

Rapid hair follicle cycling requires precise fate commitment and differentiation of hair follicle stem cells. While the essential role of transcription factors in establishing cell identity is well recognized, how cells control its protein synthesis to achieve tissue specificity remains unknown. RNA modifications constitute a pivotal layer of post-transcriptional regulation for protein synthesis. Among them, the N7-methylguanosine (m7G) modification has recently emerged as a critical regulator with diverse functional impacts. Here, we reveal a pivotal role of METTL1, the key enzyme for RNA m7G modification, in hair follicle cycle. Conditional knockout of Mettl1 in keratinocytes leads to severe hair follicle developmental dysplasia, impaired regeneration, and disrupted keratinocyte adhesion. Complementarily, keratinocyte-specific knock-in of Mettl1 accelerates hair regeneration. Mechanistically, beyond its effects on tRNAs, METTL1 deficiency destabilizes HOXC13 mRNA through internal m7G modification, which in turn downregulates the HOXC13/FOXN1/DSG4 signaling axis. Our findings establish METTL1-mediated internal mRNA m7G methylation as one of the essential regulatory layers of RNA modification in hair follicle morphogenesis and cycling, operating through the precise post-transcriptional control of a key transcriptional circuit to ensure structural integrity and timely regeneration.