Med1 deletion reprograms dental epithelium into a hair-forming epidermal architecture associated with Trp63 induction.

Ectodermal fate decisions between tooth enamel and skin hair are governed by transcriptional regulation and tissue architecture. Deletion of the Mediator subunit Med1, which links enhancer activity to transcriptional output, induces a striking lineage conversion characterized by ectopic hair formation in mouse incisors. Here, we investigated the cellular and transcriptional mechanisms underlying this process. Single-cell and spatial transcriptomic analyses revealed extensive remodeling of the incisor epithelium following Med1 deletion, whereby dental cells are converted into hair germ-like populations while retaining dental identity. Epidermal fate is associated with induction of the master regulator Trp63. Mechanistically, Med1 deletion leads to chromatin opening where TRP63 enriches at alternative MED12 containing enhancers that associate with the transcription of epidermal genes. Together, these findings suggest that Med1 loss promotes hair formation through unusual reprogramming of the dental lineage to an epidermal state rather than direct trans-differentiation to skin epithelium, providing new insights in ectodermal plasticity.