Association of epigenetic alterations in the human C7orf24 gene with the aberrant gene expression in malignant cells
Association of epigenetic alterations in the human C7orf24 gene with the aberrant gene expression in malignant cells
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DOI：
10.1093/jb/mvt063
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发表时间：
2013-10-01
影响因子：
2.7
通讯作者：
Kakeya, Hideaki
中科院分区：
文献类型：
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作者：
Ohno, Yuji;Hattori, Akira;Kakeya, Hideaki
人类7号染色体开放阅读框24（C7 orf 24）/γ-谷氨酰环转移酶已被认为是几种癌症的潜在诊断标志物，包括膀胱尿道癌、乳腺癌和子宫内膜上皮癌。我们在此研究了人类C7 orf 24启动子在正常二倍体ARPE-19和IMR-90细胞以及MCF-7和HeLa癌细胞系中的表观遗传调控，以了解恶性相关的C7 orf 24高表达的转录基础。染色质免疫沉淀分析显示，组蛋白修饰与活性染色质富集在近端区域，但不是在HeLa和MCF-7细胞的C7 orf 24启动子的远端区域。相反，与HeLa和MCF-7癌细胞中的水平相比，在ARPE-19和IMR-90细胞中观察到导致转录抑制和C7 orf 24启动子中异染色质蛋白积累的组蛋白修饰水平升高。与此同时，C7 orf 24启动子的CpG岛在正常细胞中比在癌细胞中甲基化程度更高。这些结果表明，在非恶性细胞中的C7 orf 24基因的转录沉默引起通过异染色质形成在其启动子区域;异常表达的C7 orf 24与恶性改变的结果从染色质动力学的变化。
Human chromosome 7 open reading frame 24 (C7orf24)/gamma-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells. In contrast, elevated levels of histone modifications leading to transcriptional repression and accumulation of heterochromatin proteins in the C7orf24 promoter were observed in the ARPE-19 and IMR-90 cells, compared to the levels in HeLa and MCF-7 cancer cells. In parallel, the CpG island of the C7orf24 promoter was methylated to a greater extent in the normal cells than in the cancer cells. These results suggest that the transcriptional silencing of the C7orf24 gene in the non-malignant cells is elicited through heterochromatin formation in its promoter region; aberrant expression of C7orf24 associated with malignant alterations results from changes in chromatin dynamics.