# Arginine Methylation Antagonizes TEAD3‐Mediated Repression to Promote Osteogenic Differentiation by Disrupting RUNX2‐Sequestrating Condensates

## TL;DR

Arginine methylation of TEAD3 prevents it from forming repressive structures that block bone development, allowing key bone proteins to function.

## Contribution

Discovery that arginine methylation of TEAD3 regulates osteogenic differentiation by disrupting TEAD3 condensates that sequester RUNX2.

## Key findings

- TEAD3 arginine 55 methylation disrupts condensates that repress RUNX2 activity.
- TEAD3-R55K mutation increases condensate formation and sensitivity to TEA domain inhibitors.
- Arginine methylation acts as a molecular switch for osteogenic commitment.

## Abstract

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.

In the unmethylated state, TEAD forms stable, repressive condensates that sequester the osteogenic master regulator RUNX2. Arginine methylation of TEAD at R55 acts as a molecular brake, dissolving these condensates to release RUNX2 and activate the osteogenic program.