Dancr-BRG1 regulates Nfatc1 transcription and Pgc1β- dependent metabolic shifts in osteoclastogenesis

• 成果类型: Article
• 署名作者: Zhang, Zheng; Meng, Yichen; Lin, Tao; Zhang, Zhanrong; Tao, Zhengbo; Yin, Haozan; Yang, Fu; Zhou, Xuhui
• 署名单位: Naval Medical University; Naval Medical University; Shanghai Jiao Tong University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10733
• DOI: 10.1073/pnas.2313656121
• 发表日期: 2024-01-30
• 关键词: lncrna-ancr promotes; targeting ezh2; differentiation; cells; proliferation; osteoporosis; osteoblasts; therapy

摘要

Long non- coding RNA (lncRNA) serves as a vital regulator of bone metabolism, but its role in pathologically overactive osteoclast differentiation remains elusive. Here, we identify lncRNA Dancr (Differentiation Antagonizing Non- protein Coding RNA) as a critical suppressor of osteoclastogenesis and bone resorption, which is down- regulated in response to estrogen deficiency. Global or osteoclast- specific Dancr Knockout mice display significant trabecular bone deterioration and enhanced osteoclast activity, but minimal alteration of bone formation. Moreover, the bone- targeted delivery of Dancr by Adeno- associated viral remarkably attenuates ovariectomy- induced osteopenia in mice. Mechanistically, Dancr establishes a direct interaction with Brahma- related gene 1 to prevent its binding and preserve H3K27me3 enrichment at the nuclear factor of activated T cells 1 and proliferator- activated receptor gamma coactivator 1 - beta promoters, thereby maintaining appropriate expression of osteoclastic genes and metabolic programs during osteoclastogenesis. These results demonstrate that Dancr is a key molecule maintaining proper osteoclast differentiation and bone homeostasis under physiological conditions, and Dancr overexpression constitutes a potential strategy for treating osteoporosis.