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

Yeshayahu Schlesinger; Ravid Straussman; Ilana Keshet; Shlomit Farkash; Merav Hecht; Joseph Zimmerman; Eran Eden; Zohar Yakhini; Etti Ben-Shushan; Benjamin E. Reubinoff; Yehudit Bergman; Itamar Simon; Howard Cedar

doi:10.1038/ng1950

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

Yeshayahu Schlesinger, Ravid Straussman, Ilana Keshet, Shlomit Farkash, Merav Hecht, Joseph Zimmerman, Eran Eden, Zohar Yakhini, Etti Ben-Shushan, Benjamin E. Reubinoff, Yehudit Bergman, Itamar Simon, Howard Cedar^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

994 Scopus citations

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 genome. 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 complex. In cancer cells, 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 repression.

Original language	English
Pages (from-to)	232-236
Number of pages	5
Journal	Nature Genetics
Volume	39
Issue number	2
DOIs	https://doi.org/10.1038/ng1950
State	Published - Feb 2007

Bibliographical note

Funding Information:
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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10.1038/ng1950

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

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 genome. 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 complex. In cancer cells, 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 repression.",

author = "Yeshayahu Schlesinger and Ravid Straussman and Ilana Keshet and Shlomit Farkash and Merav Hecht and Joseph Zimmerman and Eran Eden and Zohar Yakhini and Etti Ben-Shushan and Reubinoff, {Benjamin E.} and Yehudit Bergman and Itamar Simon and Howard Cedar",

note = "Funding Information: 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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doi = "10.1038/ng1950",

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AU - Farkash, Shlomit

AU - Hecht, Merav

AU - Zimmerman, Joseph

AU - Eden, Eran

AU - Yakhini, Zohar

AU - Ben-Shushan, Etti

AU - Reubinoff, Benjamin E.

AU - Bergman, Yehudit

AU - Simon, Itamar

AU - Cedar, Howard

N1 - Funding Information: 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.).

PY - 2007/2

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N2 - 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 genome. 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 complex. In cancer cells, 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 repression.

AB - 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 genome. 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 complex. In cancer cells, 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 repression.

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

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Bibliographical note

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