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<p>Osteoporosis is a complex skeletal disorder characterized by low bone mineral density (BMD). Compared with classical epigenetic modifications, such as DNA methylation and histone modifications, the participation of chromatin-remodeling complexes in osteoporosis remains less explored. To identify chromatin remodeling factors causally associated with bone mineral density (BMD), here we conducted a systematic analysis of 87 genes encoding components of four major chromatin-remodeling complexes using Summary-data-based Mendelian randomization (SMR) analysis. Candidate chromatin-remodeling factors were further cross-referenced with publicly available skeletal phenotyping data from the International Mouse Phenotyping Consortium (IMPC) database. Functional validation revealed that non-canonical BAF (ncBAF) subunit BRD9 is essential for osteoblast differentiation using both in vitro cell culture and in vivo zebrafish models. RNA-Sequencing (RNA-Seq) demonstrated that BRD9 orchestrates osteogenic differentiation by modulating Wnt/β-catenin signaling activity. Mechanistically, the osteogenic master transcription factor <i>Sp7</i> was identified as a direct transcriptional target of BRD9, whose expression is coordinately controlled through the synergistic interplay between BRD9 and Wnt/β-catenin signaling during osteogenesis. Collectively, this study established a comprehensive framework for identifying causal genes implicated in osteoporosis and elucidated the previously unrecognized regulatory role of BRD9 in osteogenesis.</p>

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Integrative analysis reveals synergistic regulation of Sp7 by BRD9 and Wnt/β-catenin signaling during osteogenic differentiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Longfei Wu,
  • Lei Wang,
  • Yan Zhuang,
  • Yuan Luo,
  • Qingyun Zhu,
  • Muyesaier Maimaitizunong,
  • Yanfei Wang,
  • Zijian Cheng,
  • Yulong Li,
  • Xinrui Sheng,
  • Mengjie Li,
  • Qi’an Luo,
  • Xiyuan Jiang,
  • Shufeng Lei,
  • Xinhua Lin,
  • Yingbin Zhong,
  • Wenyan Ren

摘要

Osteoporosis is a complex skeletal disorder characterized by low bone mineral density (BMD). Compared with classical epigenetic modifications, such as DNA methylation and histone modifications, the participation of chromatin-remodeling complexes in osteoporosis remains less explored. To identify chromatin remodeling factors causally associated with bone mineral density (BMD), here we conducted a systematic analysis of 87 genes encoding components of four major chromatin-remodeling complexes using Summary-data-based Mendelian randomization (SMR) analysis. Candidate chromatin-remodeling factors were further cross-referenced with publicly available skeletal phenotyping data from the International Mouse Phenotyping Consortium (IMPC) database. Functional validation revealed that non-canonical BAF (ncBAF) subunit BRD9 is essential for osteoblast differentiation using both in vitro cell culture and in vivo zebrafish models. RNA-Sequencing (RNA-Seq) demonstrated that BRD9 orchestrates osteogenic differentiation by modulating Wnt/β-catenin signaling activity. Mechanistically, the osteogenic master transcription factor Sp7 was identified as a direct transcriptional target of BRD9, whose expression is coordinately controlled through the synergistic interplay between BRD9 and Wnt/β-catenin signaling during osteogenesis. Collectively, this study established a comprehensive framework for identifying causal genes implicated in osteoporosis and elucidated the previously unrecognized regulatory role of BRD9 in osteogenesis.