Strathdee G, Davies B R, Vass J K, Siddiqui N, Brown R
Department of Medical Oncology, Cancer Research UK Beatson Laboratories, Glasgow University, Glasgow G61 1BD, Scotland, UK.
Carcinogenesis. 2004 May;25(5):693-701. doi: 10.1093/carcin/bgh066. Epub 2004 Jan 16.
Over 50% of human genes are associated with CpG islands and DNA methylation within such CpG islands has been clearly correlated with inhibition of expression. Whereas changes in DNA methylation play a key role in a number of human diseases, in particular cancer, in normal DNA CpG islands are nearly always methylation free, regardless of the expression status of the associated gene. Only limited evidence supports a role for DNA methylation in controlling tissue-specific expression in adult somatic tissue. Loss of expression of the MCJ gene has previously been linked to increased chemotherapeutic drug resistance in ovarian cancer. We report that loss of expression of MCJ in drug-resistant ovarian cancer cell lines depends on methylation of a CpG island within its first exon, but is independent of methylation within the promoter region. Furthermore, cell type-specific expression of the MCJ gene in normal cells also depends on the methylation status of the CpG island within its first exon. The MCJ CpG island is methylated and the gene is not expressed in cells of epithelial origin, but unmethylated and expressed in cells of lymphocyte or fibroblast origin. Chromatin immunoprecipitation assays determined that MCJ CpG island methylation was associated with loss of histone acetylation in ovarian epithelial cells compared with unmethylated fibroblast cells. Reduced acetylation was observed not only within the CpG island, but also within the promoter region, suggesting that CpG island methylation may direct alterations in chromatin structure within the promoter region, leading to gene inactivation.
超过50%的人类基因与CpG岛相关，并且此类CpG岛内的DNA甲基化已明确与基因表达抑制相关。虽然DNA甲基化变化在许多人类疾病尤其是癌症中起关键作用，但在正常DNA中，CpG岛几乎总是无甲基化的，无论相关基因的表达状态如何。仅有有限的证据支持DNA甲基化在控制成体体细胞组织特异性表达中发挥作用。MCJ基因表达缺失先前已与卵巢癌中化疗耐药性增加相关。我们报告称，耐药性卵巢癌细胞系中MCJ表达缺失取决于其第一个外显子内一个CpG岛的甲基化，但与启动子区域内的甲基化无关。此外，正常细胞中MCJ基因的细胞类型特异性表达也取决于其第一个外显子内CpG岛的甲基化状态。MCJ CpG岛在起源于上皮的细胞中是甲基化的，该基因不表达，但在起源于淋巴细胞或成纤维细胞的细胞中是未甲基化且表达的。染色质免疫沉淀分析确定，与未甲基化的成纤维细胞相比，卵巢上皮细胞中MCJ CpG岛甲基化与组蛋白乙酰化缺失相关。不仅在CpG岛内观察到乙酰化减少，在启动子区域内也观察到乙酰化减少，这表明CpG岛甲基化可能指导启动子区域内染色质结构的改变，导致基因失活。
