Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages

The transcriptional regulator Runx2 (runt-related transcription factor 2) has essential but distinct roles in os-teoblasts and chondrocytes in skeletal development. However, Runx2-mediated regulatory mechanisms un-derlying the distinctive programming of osteoblasts and chondrocytes are not well understood. Here, we perform an integrative analysis to investigate Runx2-DNA binding and chromatin accessibility ex vivo using neonatal osteoblasts and chondrocytes. We find that Runx2 engages with cell-type-distinct chromatin -accessible regions, potentially interacting with different combinations of transcriptional regulators, forming cell-type-specific hotspots, and potentiating chromatin accessibility. Genetic analysis and direct cellular re-programming studies suggest that Runx2 is essential for establishment of chromatin accessibility in osteo-blasts. Functional enhancer studies identify an Sp7 distal enhancer driven by Runx2-dependent binding and osteoblast-specific chromatin accessibility, contributing to normal osteoblast differentiation. Our findings provide a framework for understanding the regulatory landscape encompassing Runx2-mediated and cell -type-distinct enhancer networks that underlie the specification of osteoblasts.

Automated summary

This study investigated Runx2-DNA binding and chromatin accessibility in neonatal osteoblasts and chondrocytes, revealing that Runx2 interacts with cell-type-specific chromatin-accessible regions and enhances chromatin accessibility. It was found that Runx2 is essential for establishing chromatin accessibility in osteoblasts and specific enhancers driven by Runx2 contribute to normal osteoblast differentiation.