CRISPR Cas9-guided chromatin immunoprecipitation identifies miR483 as an epigenetic modulator of IGF2 imprinting in tumors.
CRISPR Cas9-guided chromatin immunoprecipitation identifies miR483 as an epigenetic modulator of IGF2 imprinting in tumors.
复制标题
CRISPR Cas9 引导的染色质免疫沉淀将 miR483 鉴定为肿瘤中 IGF2 印记的表观遗传调节剂
DOI：
10.18632/oncotarget.10918
复制
发表时间：
2017-05-23
期刊：
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Zhang Y;Hu JF;Wang H;Cui J;Gao S;Hoffman AR;Li W
正常印记胰岛素样生长因子II（IGF2）基因在多种人类恶性肿瘤中异常上调，但这种失调的机制仍然不清楚。在这份报告中，我们使用CRISPR Cas9引导的染色质免疫沉淀试验来表征参与控制人类肿瘤细胞中IGF 2基因表达的分子组分。我们发现，miR483，一种致癌内含子miRNA，结合到最上游的IGF2启动子P2。miR483的异位表达诱导IGF2表达上调，与肿瘤细胞增殖、迁移、侵袭和肿瘤集落形成的增加平行。miR483通过改变P2的表观基因型诱导IGF2印迹的丧失，降低组蛋白H3K27甲基化和降低两种印迹调节因子CTCF和SUZ12的染色质结合。本研究通过改变启动子表观基因型，确定了miR483在调节IGF2基因表达中的新作用。
The normally imprinted insulin-like growth factor II (IGF2) gene is aberrantly upregulated in a variety of human malignancies, yet the mechanisms underlying this dysregulation are still poorly defined. In this report, we used a CRISPR Cas9-guided chromatin immunoprecipitation assay to characterize the molecular components that participate in the control of IGF2 gene expression in human tumor cells. We found that miR483, an oncogenic intronic miRNA, binds to the most upstream imprinted IGF2 promoter, P2. Ectopic expression of miR483 induced upregulation of IGF2 expression, in parallel with an increase in tumor cell proliferation, migration, invasion, and tumor colony formation. miR483 induced loss of IGF2 imprinting by altering the epigenotype at P2, with reduction in histone H3K27 methylation and a decrease in chromatin binding of two imprinting regulatory factors, CTCF and SUZ12. This study identifies a new role for miR483 in the regulation of IGF2 gene expression through the alteration of the promoter epigenotype.