Epigenetic Repression of RUNX2 and OSX Promoters Controls the Nonmineralized State of the Periodontal Ligament.
Epigenetic Repression of RUNX2 and OSX Promoters Controls the Nonmineralized State of the Periodontal Ligament.
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哺乳动物牙周膜的非矿化状态是脊椎动物进化的标志之一，因为它为有效的捕食提供了弹性和非创伤性的牙齿锚定。在这里，我们试图确定关键矿化基因启动子的染色质状态如何在完全矿化的牙槽骨和牙骨质锚组织中对非矿化牙周韧带做出贡献。在发育中的小鼠牙周组织中，RUNX 2定位于牙槽骨衬里细胞，而OSX定位于整个牙周韧带的软组织。匹配的RT-PCR扩增数据和蛋白质印迹比较表明，RUNX 2和OSX骨矿化转录因子的表达在牙槽骨成骨细胞与牙周膜成纤维细胞中至少升高2.5倍。沿着RUNX 2和OSX启动子的ChIP富集数据显示，牙槽骨成骨细胞中的H3 K4 me 3标记增加，而牙周膜成纤维细胞中的H3 K9 me 3和H3 K27 me 3标记升高。在支持的表观遗传机制负责抑制矿化基因表达的牙周祖细胞，组蛋白甲基化抑制剂DZNep和毛霉素重新激活RUNX 2和OSX的表达在牙周祖细胞和碱性磷酸酶和茜素红增加，而在体内应用DZNep在大鼠上颌骨导致异常矿化的牙周膜和非矿化牙周间隙变窄。总之，这些研究表明，哺乳动物牙周膜的非矿化状态是由RUNX 2和OSX关键矿化基因启动子的表观遗传调控控制的。
The nonmineralized state of the mammalian periodontal ligament is one of the hallmarks of vertebrate evolution as it provides resilient and nontraumatic tooth anchorage for effective predation. Here we sought to determine how the chromatin state of key mineralization gene promoters contributes to the nonmineralized periodontal ligament in the midst of fully mineralized alveolar bone and cementum anchor tissues. In developing mouse periodontal tissues, RUNX2 was localized to alveolar bone–lining cells, while OSX was localized throughout the periodontal ligament’s soft tissue. Matching RT-PCR amplification data and western blot comparisons demonstrated that the expression of RUNX2 and OSX bone mineralization transcription factors was at least 2.5-fold elevated in alveolar bone osteoblasts versus periodontal ligament fibroblasts. ChIP enrichment data along the RUNX2 and OSX promoters revealed increased H3K4me3 marks in alveolar bone osteoblasts, while H3K9me3 and H3K27me3 marks were elevated in periodontal ligament fibroblasts. In support of an epigenetic mechanism responsible for the inhibition of mineralization gene expression in periodontal progenitors, histone methylation inhibitors DZNep and Chaetocin reactivated RUNX2 and OSX expression in periodontal progenitors and increased alkaline phosphatase and Alizarin Red, while the in vivo application of DZNep in rat maxillae resulted in aberrant mineralization in the periodontal ligament and a narrowing of the nonmineralized periodontal space. Together, these studies demonstrate that the nonmineralized state of the mammalian periodontal ligament is controlled by an epigenetic regulation of the RUNX2 and OSX key mineralization gene promoters.
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