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Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer

Nature Genetics volume 39, pages 232–236 (2007)Cite this article

Abstract

Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome1. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex2,3. In cancer cells4, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression2.

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Figure 1: Caco-2 methylated genes are packaged with trimethylated H3K27.
Figure 2: Genes methylated in cancer are marked by Polycomb components.
Figure 3: Targeted genes are associated with DNMTs in Caco-2 cells.
Figure 4: Tumor suppressor genes.

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Acknowledgements

We thank Y. Zhang for antibody to trimethylated H3K27. This work was supported by grants from the US National Institutes of Health, the Israel Cancer Research Fund, the Rosetrees Trust, Lewis Sanders, the Prostate Cancer Foundation and both Philip Morris USA Inc. and Philip Morris International (H.C. and R.S.).

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Authors and Affiliations

  1. Department of Cellular Biochemistry and Human Genetics, The Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel

    Yeshayahu Schlesinger, Ravid Straussman, Ilana Keshet, Merav Hecht & Howard Cedar

  2. Department of Molecular Biology, The Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel

    Shlomit Farkash & Itamar Simon

  3. Department of Gastroenterology, The Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel

    Joseph Zimmerman

  4. Department of Computer Sciences, Technion–Israel Institute of Technology, Haifa, 32000, Israel

    Eran Eden & Zohar Yakhini

  5. Agilent Technologies, Tel Aviv, 49527, Israel

    Zohar Yakhini

  6. Department of Obstetrics and Gynecology & The Goldyn Savad Institute of Gene Therapy, The Hebrew University–Hadassah Medical School, Jerusalem, 91120

    Etti Ben-Shushan & Benjamin E Reubinoff

  7. Department of Experimental Medicine, The Hebrew University–Hadassah Medical School, Jerusalem, 91120

    Yehudit Bergman

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Correspondence to Howard Cedar.

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Supplementary information

Supplementary Fig. 1

Methylated genes are packaged with trimethylated H3K27 in Caco-2. (PDF 23 kb)

Supplementary Fig. 2

Histone modification of genes methylated in cancer. (PDF 99 kb)

Supplementary Table 1

Bioinformatic confirmation of trimethylated H3K27 ChIP. (PDF 77 kb)

Supplementary Table 2

General association of Polycomb components with genes methylated in cancer. (PDF 49 kb)

Supplementary Table 3

Association of Polycomb components with genes methylated in cancer. (PDF 51 kb)

Supplementary Table 4

Genes marked with Polycomb reported to be hypermethylated in cancer. (PDF 65 kb)

Supplementary Table 5

PCR primer sequences. (PDF 31 kb)

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Schlesinger, Y., Straussman, R., Keshet, I. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39, 232–236 (2007). https://doi.org/10.1038/ng1950

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