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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    ABSTRACT: Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non‑gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.
    Molecular Medicine Reports 05/2014; 10(1). DOI:10.3892/mmr.2014.2221 · 1.55 Impact Factor
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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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    ABSTRACT: Like other cancers, most gynecologic cancers caused by aberrant expression of cancer-related genes. Epigenetics is one of important gene expression mechanisms which contribute to cancer development and progression by regulating cancer-related genes. Since the discovery of differential gene expression patterns in cancer cells compared with normal cells, extensive efforts have been made to explore the origins of abnormal gene expression in cancer. Epigenetics, the study inheritable changes in gene expression that do not alter DNA sequence, is a key area of this research. DNA methylation and histone modification are well-known epigenetic mechanisms, microRNAs and alternative splicing have recently been identified as important regulators of epigenetic changes. These epigenetic mechanisms not only affect specific target gene expression but also regulate the functioning of other epigenetic mechanisms. Moreover, these diverse epigenetic regulations occur simultaneously. Epigenetic regulation of gene expression is extraordinarily complicated and requires that all epigenetic mechanisms be studied at once to determine the exact gene regulation mechanisms. Traditionally, the contribution of epigenetics to cancer is thought to be mediated through the inactivation of tumor suppressor genes (TSGs) expression. But recently it is arising that some oncogenes or cancer-promoting genes (CPGs) are overexpressed in diverse type of cancers through epigenetic derepression mechanism, such as DNA demethylation, histone demethylation. Epigenetic derepression arises from diverse epigenetic changes, and all of these mechanisms are actively interact each other to increase oncogenes or CPGs expression in cancer cell. Oncogenes or CPGs overexpressed through epigenetic derepression can initiate cancer development, and the accumulation of these abnormal epigenetic changes makes cancer more aggressive and resistant to treatment. This review discusses epigenetic mechanisms involved in the overexpress
    Frontiers in Oncology 02/2014; 4:12. DOI:10.3389/fonc.2014.00012
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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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    ABSTRACT: BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.
    Neoplasia (New York, N.Y.) 05/2013; 15(5):511-22. DOI:10.1593/neo.121784 · 4.25 Impact Factor
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