# Basonuclin-2 promotes fracture repair through NuRD-dependent chromatin remodeling in periosteal stem cells

## TL;DR

Basonuclin-2 (BNC2) helps repair bone fractures by regulating stem cell activity and chromatin changes in mice.

## Contribution

BNC2 is identified as a novel regulator of periosteal stem cell expansion and fracture repair through NuRD-dependent chromatin remodeling.

## Key findings

- BNC2 marks quiescent periosteal cells and is upregulated during fracture repair.
- BNC2 depletion impairs stem cell proliferation and fracture healing in mice.
- BNC2 promotes chromatin accessibility and histone acetylation for gene activation.

## Abstract

Bone fracture healing remains a significant challenge in orthopedics, as injury-responsive skeletal stem cell (SSC) populations and the regulatory mechanisms governing SSC activation during nonunion fracture repair remain poorly delineated. This study identifies zinc finger transcription factor basonuclin-2 (BNC2) as a skeletal fracture repair control factor in periosteal stem cells. BNC2 marks quiescent periosteal cells during homeostasis and is significantly upregulated upon injury in mice, driving endochondral ossification post-fracture via clonal expansion. Moreover, knockout of Bnc2 in Prx1-cre+ cells (not Ocn-cre+ osteoblasts or LepR-creER+ BMSCs) resulted in impaired fracture healing, suppressing SSC proliferation. Mechanistically, ATAC-seq revealed that BNC2 deletion reduced chromatin accessibility at promoter regions of proliferation genes, hindering transcriptional activation. Additionally, BNC2 regulates histone H3 acetylation by interacting with the NuRD complex. Pharmacologically inhibition of HDAC1/2 activity partially ameliorated the fracture repair defects observed in Prx1-cre; Bnc2f/f mice. Collectively, we identified BNC2+ cells as a rapidly expanding periosteal cell population inducing endochondral ossification niches during repair, providing potential therapeutic strategies for nonunion fractures.

Skeletal stem cell (SSC) populations induced upon injury and regulatory mechanisms governing fracture repair remain poorly defined. This study identifies transcription factor basonuclin-2 (BNC2) as an injury-induced regulator of SCC expansion and bone fracture repair.

BNC2 labels quiescent periosteal cells during homeostasis.BNC2 depletion in Prx1+ periosteal cells impairs cell proliferation and fracture healing in mice.BNC2 increases chromatin accessibility and transcriptional activation of proliferation genes by elevating histone H3 acetylation in NuRD complex-dependent manner.

BNC2 labels quiescent periosteal cells during homeostasis.

BNC2 depletion in Prx1+ periosteal cells impairs cell proliferation and fracture healing in mice.

BNC2 increases chromatin accessibility and transcriptional activation of proliferation genes by elevating histone H3 acetylation in NuRD complex-dependent manner.

Transcription factor BNC2 promotes injury-induced expansion of Prx1+ periosteal cells for endochondral ossification and skeletal fracture repair.