Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer.
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.
Schlesinger
Yeshayahu
Y
Department of Cellular Biochemistry and Human Genetics, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Straussman
Ravid
R
Keshet
Ilana
I
Farkash
Shlomit
S
Hecht
Merav
M
Zimmerman
Joseph
J
Eden
Eran
E
Yakhini
Zohar
Z
Ben-Shushan
Etti
E
Reubinoff
Benjamin E
BE
Bergman
Yehudit
Y
Simon
Itamar
I
Cedar
Howard
H
D018938:Caco-2 Cells; D002352:Carrier Proteins; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D014759:Viral Envelope Proteins
D002352:Carrier Proteins; D006657:Histones; D014759:Viral Envelope Proteins; C406065:envelope H3L protein, Vaccinia virus; D008780:Methyltransferases; D008239:Lysine