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Molecular and Cellular Biology, June 2004, p. 4781-4790, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4781-4790.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Promoter-Dependent Mechanism Leading to Selective Hypomethylation within the 5' Region of Gene MAGE-A1 in Tumor Cells

Charles De Smet,* Axelle Loriot, and Thierry Boon

Ludwig Institute for Cancer Research, Brussels Branch, and Cellular Genetics Unit, Université Catholique de Louvain, B1200 Brussels, Belgium

Received 23 December 2003/ Returned for modification 23 February 2004/ Accepted 14 March 2004

Several male germ line-specific genes, including MAGE-A1, rely on DNA methylation for their repression in normal somatic tissues. These genes become activated in many types of tumors in the course of the genome-wide demethylation process which often accompanies tumorigenesis. We show that in tumor cells expressing MAGE-A1, the 5' region is significantly less methylated than the other parts of the gene. The process leading to this site-specific hypomethylation does not appear to be permanent in these tumor cells, since in vitro-methylated MAGE-A1 sequences do not undergo demethylation after being stably transfected. However, in these cells there is a process that inhibits de novo methylation within the 5' region of MAGE-A1, since unmethylated MAGE-A1 transgenes undergo remethylation at all CpGs except those located within the 5' region. This local inhibition of methylation appears to depend on promoter activity. We conclude that the site-specific hypomethylation of MAGE-A1 in tumor cells relies on a transient process of demethylation followed by a persistent local inhibition of remethylation due to the presence of transcription factors.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Brussels Branch, 74 Avenue Hippocrate, B1200 Brussels, Belgium. Phone: 32-2-7647443. Fax: 011-32-02-7629405. E-mail: charles.desmet{at}bru.licr.org.

Molecular and Cellular Biology, June 2004, p. 4781-4790, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4781-4790.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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