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Evidence for an instructive mechanism of de novo methylation in cancer cells

Nature Genetics volume 38, pages 149–153 (2006)Cite this article

Abstract

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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Figure 1: Detection of DNA methylation by mDIP.
Figure 2: mDIP microarray analysis.
Figure 3: Genomic analysis of methylated genes in cancer cells.
Figure 4: Effect of methylation on gene expression.

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Acknowledgements

Colon biopsies were provided by J. Zimmerman. We thank R. Rubinstein and M. Kott for help in the computer and microarray analyses. This research was supported by grants from the Rosetrees Trust, the US National Institutes of Health, the Israel Cancer Research Fund, the Belfer Foundation, the Conquer Fragile X Foundation, the Prostate Cancer Foundation, Fondation pour la Recherche Medicale-Ligue Nationale Francaise Contre le Cancer, Association for International Cancer Research (AICR) and the Bikura program of the Israel Science Foundation.

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Authors and Affiliations

  1. Department of Cellular Biochemistry and Human Genetics,

    Ilana Keshet, Yeshayahu Schlesinger, Shlomit Farkash, Eyal Rand, Merav Hecht, Eli Pikarski, Howard Cedar & Itamar Simon

  2. Department of Molecular Biology,

    Ilana Keshet, Yeshayahu Schlesinger, Shlomit Farkash, Eyal Rand, Merav Hecht, Eli Pikarski, Howard Cedar & Itamar Simon

  3. Department of Pathology of Hebrew University, Jerusalem, Israel

    Ilana Keshet, Yeshayahu Schlesinger, Shlomit Farkash, Eyal Rand, Merav Hecht, Eli Pikarski, Howard Cedar & Itamar Simon

  4. Center for Studies in Physics and Biology, Rockefeller University, New York, New York, USA

    Eran Segal

  5. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA

    Richard A Young

  6. Laboratoire de Virologie Structurale et Moleculaire, Universite Fourier de Grenoble, Avenue Gresivandan, La Tronche, France

    Alain Niveleau

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Correspondence to Howard Cedar.

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Supplementary information

Supplementary Fig. 1

Sensitivity of microarray mDIP for detecting DNA methylation. (PDF 285 kb)

Supplementary Fig. 2

Bisulfite analysis of methylated genes. (PDF 1060 kb)

Supplementary Table 1

Methylated genes previously reported. (PDF 56 kb)

Supplementary Table 2

Methylated gene characteristics. (PDF 57 kb)

Supplementary Table 3

Functional categories of methylated genes. (PDF 73 kb)

Supplementary Table 4

mDIP microarray data. (PDF 7514 kb)

Supplementary Method (PDF 51 kb)

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Keshet, I., Schlesinger, Y., Farkash, S. et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 38, 149–153 (2006). https://doi.org/10.1038/ng1719

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