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Using summary-data-based Mendelian randomization across 87 genes from four major chromatin-remodeling complexes and validating candidates with International Mouse Phenotyping Consortium data, the study identifies BRD9 (ncBAF) as essential for osteoblast differentiation. Mechanistically, BRD9 activates osteogenesis by coordinating Wnt/β-catenin signaling to transcriptionally regulate the osteogenic master factor Sp7.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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[https://doi.org/10.1038/s42003-025-09278-z](https://doi.org/10.1038/s42003-025-09278-z) |  |  |\n| Integrative analysis reveals synergistic regulation of Sp7 by BRD9 and Wnt/β-catenin signaling during osteogenic differentiation\u003Cbr> Check for updates |  |  |\n| Longfei Wu 1,9 , Lei Wang1,9, Yan Zhuang2,9, Yuan Luo3,9, Qingyun Zhu1,4, Muyesaier Maimaitizunong2, Yanfei Wang1, Zijian Cheng 1, Yulong Li5,6, Xinrui Sheng1, Mengjie Li4, Qi’an Luo4, Xiyuan Jiang7, Shufeng Lei1, Xinhua Lin4,6, Yingbin Zhong 2,8  & Wenyan Ren 4  |  |  |\n| 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. RNASequencing (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. |  |  |\n| Osteoporosis is a complex multifactorial skeletal disorder characterized by low bone mineral density (BMD) and increased fracture risk1. Both genetic alternation and environmental stimuli, including diet, physical activity, and air pollution, collectively influence bone remodeling processes2,3. Epigenetic mechanisms mediate the interplay between genetic factors and | environmental stimuli, playing a pivotal role in bone homeostasis4. DNA methylation and histone modifications have been extensively investigated in the pathogenesis of osteoporosis5,6. However, chromatin remodeling, another crucial epigenetic mechanism, has not received as much attention in this context. ATP-dependent chromatin-remodeling complexes regulate |  |\n\n1Center for Genetic Epidemiology and Genomics, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, China. 2Taicang Affiliated Hospital, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China. 3Taicang Affiliated Hospital of Soochow University, Suzhou, China. 4Cambridge-Suda Genomic Resource Center, Suzhou Medical College of Soochow University, Suzhou, China. 5School of Life Sciences, Inner Mongolia University, Hohhot, China. 6School of Life Sciences, Fudan University, Shanghai, China. 7Center of Osteoporosis, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China. 8MOE Key Laboratory of Geriatric Diseases and Immunology, School of Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China. 9These authors contributed equally: Longfei Wu, Lei Wang, Yan Zhuang, Yuan Luo. e-mail: [lfwu@suda.edu.cn](lfwu@suda.edu.cn); [ybzhongsd@suda.edu.cn](ybzhongsd@s","cbCaitNtu2hy9aw7","https://ap.wps.com/l/cbCaitNtu2hy9aw7","pdf",3892560,15,"English","# Background\n## Epigenetic regulation in osteoporosis\n# Methods\n## Summary-data-based Mendelian randomization and IMPC cross-referencing\n## Functional validation models\n# Findings\n## BRD9 is essential for osteoblast differentiation\n## Wnt/β-catenin activity is modulated by BRD9\n## Sp7 as a direct transcriptional target","[{\"question\":\"What was the main goal of the study regarding osteoporosis?\",\"answer\":\"To identify chromatin remodeling factors causally associated with bone mineral density by combining genetic discovery with functional validation.\"},{\"question\":\"How did the researchers prioritize candidate genes?\",\"answer\":\"They performed summary-data-based Mendelian randomization using components of four major chromatin-remodeling complexes, then cross-referenced candidates with skeletal phenotyping data from the IMPC database.\"},{\"question\":\"What role does BRD9 play during osteogenic differentiation?\",\"answer\":\"Functional validation showed that BRD9, a non-canonical BAF (ncBAF) subunit, is essential for osteoblast differentiation.\"}]","Integrative analysis reveals synergistic regulation of Sp7 by BRD9 and Wnt/β-catenin signaling during osteogenic differentiation | PDF",1790732867,38]