Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8.
Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8.
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DOI：
10.4049/jimmunol.1501466
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Ivashkiv LB
中科院分区：
文献类型：
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作者：
Fang C;Qiao Y;Mun SH;Lee MJ;Murata K;Bae S;Zhao B;Park-Min KH;Ivashkiv LB
破骨细胞是骨吸收细胞，对动态平衡的骨重建和病理性骨吸收具有重要作用。新出现的证据表明，表观遗传机制在破骨细胞形成中起着重要作用。最近的一项研究表明，破骨细胞分化需要通过DNA甲基化使破骨细胞生成负调控因子IRF8的表观遗传学沉默。在这项研究中，我们研究了EZH2，它通过组蛋白甲基化在表观遗传上沉默基因表达，在破骨细胞形成中的作用。通过小分子GSK126抑制EZH2，或使用反义寡核苷酸降低其表达，阻碍了破骨细胞的分化。机制上，在RANKL刺激后，EZH2被募集到IRF8启动子上，以沉积负组蛋白标记H3K27me3，并下调IRF8的表达。GSK126减少绝经后骨质疏松症去卵巢小鼠模型的骨丢失。我们的发现为在破骨细胞形成过程中表观遗传的IRF8沉默的另一种机制提供了证据，该机制可能与DNA甲基化协同作用，进一步强调了IRF8作为破骨细胞形成的负调控因子的重要性。
Osteoclasts are resorptive cells important for homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic mechanisms in osteoclastogenesis. A recent study showed that epigenetic silencing of the negative regulator of osteoclastogenesis Irf8 by DNA methylation is required for osteoclast differentiation. In this study, we investigated the role of EZH2, which epigenetically silences gene expression by histone methylation, in osteoclastogenesis. Inhibition of EZH2 by the small molecule GSK126, or decreasing its expression using antisense oligonucleotides, impeded osteoclast differentiation. Mechanistically, EZH2 was recruited to the IRF8 promoter after RANKL stimulation to deposit the negative histone mark H3K27me3 and downregulate IRF8 expression. GSK126 attenuated bone loss in the ovariectomy mouse model of postmenopausal osteoporosis. Our findings provide evidence for an additional mechanism of epigenetic IRF8 silencing during osteoclastogenesis that likely works cooperatively with DNA methylation, further emphasizing the importance of IRF8 as a negative regulator of osteoclastogenesis.