Demethylation of Epiregulin Gene by Histone Demethylase FBXL11 and BCL6 Corepressor Inhibits Osteo/dentinogenic Differentiation
Demethylation of Epiregulin Gene by Histone Demethylase FBXL11 and BCL6 Corepressor Inhibits Osteo/dentinogenic Differentiation
复制标题
组蛋白去甲基化酶 FBXL11 和 BCL6 辅阻遏物对上皮调节蛋白基因的去甲基化抑制骨/牙本质分化
DOI：
10.1002/stem.1255
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发表时间：
2013-01-01
期刊：
影响因子：
5.2
通讯作者：
Fan, Zhipeng
中科院分区：
文献类型：
--
作者：
Du, Juan;Ma, Yushi;Fan, Zhipeng
间充质干细胞（MSC）是一种可靠的组织再生资源，但定向分化的分子机制仍不清楚，这限制了潜在的MSC应用。由组蛋白甲基转移酶和去甲基化酶控制的组蛋白甲基化可能在MSC分化中起关键作用。在这里，我们研究了FBXL 11，一种组蛋白脱甲基酶，赖氨酸（K）特异性脱甲基酶2A，它在进化上保守，广泛表达，是含JmjC结构域的组蛋白脱甲基酶家族的成员。我们通过功能获得和功能丧失试验测试FBXL 11是否可以抑制MSC细胞中的成骨/牙本质分化潜能。我们发现FBXL 11调节MSC细胞的成骨/牙本质分化。此外，我们发现编码表皮生长因子的基因，上皮调节蛋白（EREG），是FBXL 11的下游靶点，EREG介导FBXL 11调节MSC分化。此外，我们发现FBXL 11的组蛋白去甲基化酶功能通过与BCL 6辅阻遏物结合而被激活，并且该复合物可以通过增加EREG启动子中组蛋白K4/36甲基化来抑制EREG转录。总之，我们的研究结果阐明了FBXL 11和EREG的新功能，探索了MSC细胞定向分化的分子机制，并确定了改善组织再生技术的潜在靶基因。干细胞2013;31：126-136
Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but the molecular mechanism underlying directed differentiation remains unclear; this has restricted potential MSC applications. Histone methylation, controlled by histone methyltransferases and demethylases, may play a key role in MSC differentiation. Here, we investigated FBXL11, a histone demethylase, lysine (K)‐specific demethylase 2A, which is evolutionarily conserved, ubiquitously expressed, and a member of the JmjC‐domain‐containing histone demethylase family. We tested whether FBXL11 could inhibit the osteo/dentinogenic differentiation potential in MSC cells with gain‐ and loss‐of‐function assays. We found that FBXL11 regulated osteo/dentinogenic differentiation in MSC cells. Furthermore, we found that the gene encoding the epidermal growth factor, Epiregulin (EREG), was a downstream target of FBXL11, and that EREG mediated FBXL11 regulation of MSC differentiation. Moreover, we found that the FBXL11 histone demethylase function was activated by associating with BCL6 corepressor, and this complex could repress EREG transcription by increasing histone K4/36 methylation in the EREG promoter. In conclusion, our results elucidated a new function for FBXL11 and EREG, explored the molecular mechanism underlying directed differentiation in MSC cells, and identified potential target genes for improving tissue regeneration techniques. STEM Cells2013;31:126–136