Carcinogenesis Advance Access originally published online on January 16, 2004
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Carcinogenesis, Vol. 25, No. 5, 693-701,
May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.
ARTICLE |
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, UK, 1 Department of Surgery, The Medical School, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, UK, 2 Beatson Institute for Cancer Research, Cancer Research Beatson Laboratories, Glasgow G61 1BD, UK and 3 Department of Gynaecological Oncology, Stobhill Hospital, Glasgow G21 3UW, UK
4 To whom correspondence should be addressed. Tel: +44 141 330 3509; Fax: +44 141 330 4127; Email: g.strathdee{at}beatson.gla.ac.uk
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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