Cell type-specific methylation of an intronic CpG Island controls expression of the MCJ gene

Department of Medical Oncology, Cancer Research UK Beatson Laboratories, Glasgow University, Glasgow G61 1BD, Scotland, UK.
Carcinogenesis (Impact Factor: 5.33). 06/2004; 25(5):693-701. DOI: 10.1093/carcin/bgh066
Source: PubMed


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.

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    • "Upregulation, together with hypomethylation of the ABCG2 multidrug transporter and TUBB3 genes, which is a determinant of taxane resistance, have been observed in cases of advanced ovarian carcinoma with drug-acquired chemoresistance (64,65). Other cancer-associated genes including MCJ (66,67) and SNGG (synucelin-γ), encoding an activator of the MAPK and Elk-1 signaling cascades (63,68), are upregulated in ovarian cancer in association with DNA hypomethylation. "
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    • "Epigenetic changes in cancer also provide prognostic information. In ovarian cancer, reduced expression of the methylation-controlled DNAJ gene (MCJ) owing to DNA hypermethylation increases chemotherapeutic drug resistance (134, 135). Interestingly, the CpG Island in exon 1 of MCJ is more critical than the promoter region CpG Island for gene repression. "
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    • "The DNA methylation profile of tumors is frequently characterized by global hypomethylation and simultaneous hypermethylation of CpG islands [5] [6]. It is known that, when methylation is localized in the promoter [7], in the 5′ untranslated region (5′UTR), or in the first exons/introns [8] [9] [10] of a gene, methylation and transcription of that gene are usually inversely correlated. Methylation of tumor suppressor genes often leads to their down-regulation, potentially playing a pathogenic role in the development of cancer and in resistance to apoptosis-inducing drugs [11]. "
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