Histone methyltransferase NSD1 maintains Egr1 expression to orchestrate primary/reactionary dentinogenesis

Dentinogenesis is a highly coordinated process orchestrated by odontoblasts that is not only critical for tooth development but also essential for pulp vitality after injury. Although the signaling pathways regulating this process have been well characterized, it remains elusive how dentinogenesis is epigenetically regulated during tooth development and adulthood. Here, we show that nuclear receptor binding SET domain protein 1 (NSD1), a histone methyltransferase catalyzing the dimethylation of histone H3 at lysine 36 (H3K36me2), exhibits dynamic spatiotemporal expression patterns during odontoblast differentiation as well as injury response. Conditional knockout of Nsd1 in the odontoblasts of neonatal mice, driven by rAAV6-Col2.3-Cre, led to decreased dentin thickness, defective mineral deposition, and the downregulation of odontoblast differentiation markers. Consistently, Nsd1 deletion in adult mice impaired reactionary dentin formation after injury. Mechanistically, transcriptomic profiling of mouse dental papilla cells identified early growth response 1 (EGR1) as a key downstream target of NSD1, which in turn modulated the expression of many genes downregulated upon Nsd1 knockdown by RNA-seq analysis. The Egr1 locus was tightly enriched with H3K36me2, which controlled its expression and further activated Col1a1, an extracellular matrix component. Upon injury, the expression of NSD1/H3K36me2 and EGR1 was rapidly induced to facilitate reactionary dentinogenesis to protect the inner dental pulp. Collectively, our findings support a potential role for the NSD1/H3K36me2–EGR1 axis in initiating both primary and reactionary dentin matrix formation.