4.8 Article

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

Journal

CELL REPORTS
Volume 40, Issue 10, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2022.111315

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Funding

  1. JSPS [16H06279, 17H05106, 18K19636, 20H03885, 21H04952, 17H04403, 21H03142]
  2. Rising Star Awards from the American Society for Bone and Mineral Research
  3. Mochida Memorial Foundation
  4. Uehara Memorial Foundation
  5. Takeda Science Foundation Research Grant
  6. Japan Agency for Medical Research and Development (AMED) [JP21bm0704071, JP21zf0127002]
  7. Japan Science and Technology Agency through the Center of Innovation Program [JPMJCE1304]
  8. National Institutes of Health [DK056246]

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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.
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.

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