Arginine Methylation Antagonizes TEAD3-Mediated Repression to Promote Osteogenic Differentiation by Disrupting...

Osteogenic differentiation is essential for bone remodeling and repair. Protein arginine methyltransferases (PRMTs) regulate this process; however, their key substrates and mechanisms remain elusive. Here, we identify TEAD3, a TEA domain transcription factor mediating Hippo signaling output, as an arginine-methylated regulator of periodontal ligament stem cells (PDLSCs) osteogenesis. Mechanistically, TEAD3 is methylated at arginine 55 (R55), a conserved residue within its DNA-binding TEA domain. Disruption of R55 methylation via R55K mutation enhances formation of TEAD3 homodimer condensates, which spatially constrain RUNX2 transcriptional activity without disrupting its Hippo signaling functions. Notably, the TEAD3-R55K mutant exhibits heightened sensitivity to TEAi, a TEA domain- targeting inhibitory peptide. These findings unveil arginine methylation as a critical switch governing TEAD3-mediated osteogenic commitment and highlight TEAD-targeted strategies as promising therapeutics for bone regeneration.