Nature Genetics 38, 149 - 153 (2006)
Published online: 24 January 2006; | doi:10.1038/ng1719
Evidence for an instructive mechanism of de novo methylation in cancer cellsIlana Keshet1, Yeshayahu Schlesinger1, Shlomit Farkash1, Eyal Rand1, Merav Hecht1, Eran Segal2, Eli Pikarski1, Richard A Young3, Alain Niveleau4, Howard Cedar1
& Itamar Simon11
Ilana Keshet, Yeshayahu Schlesinger, Eyal Rand, Merav Hecht and Howard Cedar are at the Department of Cellular Biochemistry and Human Genetics; Shlomit Farkash and Itamar Simon are at the Department of Molecular Biology; and Eli Pikarski is at the Department of Pathology of Hebrew University, Jerusalem, Israel. 2
Eran Segal is at the Center for Studies in Physics and Biology, Rockefeller University, New York, New York, USA. 3
Richard A. Young is at the Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA. 4
Alain Niveleau is at the Laboratoire de Virologie Structurale et Moleculaire, Universite Fourier de Grenoble, Avenue Gresivandan, La Tronche, France.
Correspondence should be addressed to Howard Cedar cedar@md.huji.ac.il DNA methylation has a role in the regulation of gene expression during normal mammalian development but can also mediate epigenetic silencing of CpG island genes in cancer and other diseases. Many individual genes (including tumor suppressors) have been shown to undergo de novo methylation in specific tumor types, but the biological logic inherent in this process is not understood. To decipher this mechanism, we have adopted a new approach for detecting CpG island DNA methylation that can be used together with microarray technology. Genome-wide analysis by this technique demonstrated that tumor-specific methylated genes belong to distinct functional categories, have common sequence motifs in their promoters and are found in clusters on chromosomes. In addition, many are already repressed in normal cells. These results are consistent with the hypothesis that cancer-related de novo methylation may come about through an instructive mechanism.
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