Epigenetic alterations contribute to promoter activity of imprinting gene IGF2.
Epigenetic alterations contribute to promoter activity of imprinting gene IGF2.
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DOI：
10.1016/j.bbagrm.2017.12.007
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发表时间：
2018-02
期刊：
影响因子：
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通讯作者：
Qi-Fan Zheng;Bin Xu;Hui-Min Wang;Li-hong Ding;Jin-Yang Liu;Ling-Yu Zhu;Huan Qiu;Li Zhang;Guang-Yi Ni;Jing Ye;Shu-Bin Gao;G. Jin
中科院分区：
文献类型：
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作者：
Qi-Fan Zheng;Bin Xu;Hui-Min Wang;Li-hong Ding;Jin-Yang Liu;Ling-Yu Zhu;Huan Qiu;Li Zhang;Guang-Yi Ni;Jing Ye;Shu-Bin Gao;G. Jin
胰岛素样生长因子2（IGF 2）是一个经典的印迹基因，其表达与肝癌的印迹特征并不完全相关。启动子活性在调节IGF 2中的重要机制尚未完全阐明。我们发现，IGF 2启动子的menin-MLL复合物修饰的组蛋白3赖氨酸4三甲基化（H3 K4 me 3）有助于IGF 2的启动子活性。在具有IGF 2的稳健表达的Hep 3B细胞中观察到menin和在DNA去甲基化的P3/4启动子处的丰富的H3 K4 me 3的强结合。在IGF 2低表达的HepG 2细胞中，menin不与DNA高甲基化的P3/4区域结合;然而，menin过表达抑制DNA甲基化，并促进HepG 2中P3/4的H3 K4 me 3以及IGF 2的表达。此外，P3/4位点的H3 K4 me 3在IGF 2高表达的原发性HCC标本中被激活。此外，通过MI-2/3抑制menin/MLL相互作用可降低IGF 2表达，抑制IGF 1 R-AKT通路，并显著抑制HCC，同时IGF 2表达增强。综上所述，我们认为menin-MLL复合物介导的P3/4位点的H3 K4 me 3是一种新的IGF 2释放的表观遗传机制。
The expression of insulin-like growth factor 2 (IGF2), a classical imprinting gene, didn't completely correlate with its imprinting profiles in hepatocellular carcinoma (HCC). The mechanistic importance of promoter activity in regulation ofIGF2has not been fully clarified. Here we show that histone 3 lysine 4 trimethylation (H3K4me3) modified by menin-MLL complex ofIGF2promoter contributes to promoter activity ofIGF2. The strong binding of menin and abundant H3K4me3 at the DNA demethylated P3/4 promoters were observed in Hep3B cells with the robust expression ofIGF2. InIGF2-low-expressing HepG2 cells, menin didn't bind to DNA hypermethylated P3/4 regions; however, menin overexpression inhibited DNA methylation and promoted H3K4me3 at the P3/4 as well asIGF2expression in HepG2. In addition, the H3K4me3 at P3/4 locus was activated in primary HCC specimens with highIGF2expression. Furthermore, inhibition of the menin/MLL interaction via MI-2/3 reducedIGF2expression, inhibited the IGF1R-AKT pathway, and significantly repressed HCC with robust expression ofIGF2. Taken together, we conclude that H3K4me3 of P3/4 locus mediated by the menin-MLL complex is a novel epigenetic mechanism for releasingIGF2.