Chen Bailing, Yu Miaomiao, Chang Qingshan, Lu Yongju, Thakur Chitra, Ma Danjun, Yi Zhenping, Chen Fei
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, 259 Mack Avenue, Detroit, MI, USA.
Oncotarget. 2013 Sep;4(9):1427-37. doi: 10.18632/oncotarget.1155.
Mineral dust-induced gene (mdig) had been linked to the development of human lung cancers associated with environmental exposure to mineral dust, tobacco smoke or other carcinogens. In the present studies, we demonstrated that the overexpression of mdig in A549 adenocarcinomic human alveolar type II epithelial cells decreases the heterochromatin conformation of the cells and de-represses the transcription of genes in the tandemly repeated DNA regions. Although mdig can only cause a marginal decrease of the total histone H3 lysine 9 trimethylation (H3K9me3), a significant reduction of H3K9me3 in the promoter region of H19, the paternally imprinted but maternally expressed gene transcribing a large intergenic non-coding RNA (lincRNA), was observed in the cells with mdig overexpression. Silencing mdig by either shRNA or siRNA not only increased the level of H3K9me3 in the promoter region of H19 but also attenuated the transcription of H19 long non-coding RNA. Demethylation assays using immunoprecipitated mdig and histone H3 peptide substrate suggested that mdig is able to remove the methyl groups from H3K9me3. Clinically, we found that higher levels of mdig and H19 expression correlate with poorer survival of the lung cancer patients. Taken together, our results imply that mdig is involved in the regulation of H3K9me3 to influence the heterochromatin structure of the genome and the expression of genes important for cell growth or transformation.
矿物粉尘诱导基因（mdig）与人类肺癌的发生发展有关，这些肺癌与环境暴露于矿物粉尘、烟草烟雾或其他致癌物相关。在本研究中，我们证明mdig在A549人II型肺泡腺癌上皮细胞中的过表达会降低细胞的异染色质构象，并解除串联重复DNA区域中基因的转录抑制。虽然mdig只能使总组蛋白H3赖氨酸9三甲基化（H3K9me3）略有降低，但在mdig过表达的细胞中，观察到H19启动子区域的H3K9me3显著减少，H19是一个父本印记但母本表达的基因，转录一种大型基因间非编码RNA（lincRNA）。通过shRNA或siRNA沉默mdig不仅增加了H19启动子区域的H3K9me3水平，还减弱了H19长链非编码RNA的转录。使用免疫沉淀的mdig和组蛋白H3肽底物进行的去甲基化分析表明，mdig能够从H3K9me3上去除甲基基团。临床上，我们发现较高水平的mdig和H19表达与肺癌患者较差的生存率相关。综上所述，我们的结果表明mdig参与H3K9me3的调控，以影响基因组的异染色质结构以及对细胞生长或转化重要的基因的表达。
