Methylation of polycomb target genes in intestinal cancer is mediated by inflammation.
Epigenetic changes are strongly associated with cancer development. DNA hypermethylation is associated with gene silencing and is often observed in CpG islands. Recently, it was suggested that aberrant CpG island methylation in tumors is directed by Polycomb (PcG) proteins. However, specific mechanisms responsible for methylation of PcG target genes in cancer are not known. Chronic infection and inflammation contribute to up to 25% of all cancers worldwide. Using glutathione peroxidase, Gpx1 and Gpx2, double knockout (Gpx1/2-KO) mice as a model of inflammatory bowel disease predisposing to intestinal cancer, we analyzed genome-wide DNA methylation in the mouse ileum during chronic inflammation, aging, and cancer. We found that inflammation leads to aberrant DNA methylation in PcG target genes, with 70% of the approximately 250 genes methylated in the inflamed tissue being PcG targets in embryonic stem cells and 59% of the methylated genes being marked by H3K27 trimethylation in the ileum of adult wild-type mice. Acquisition of DNA methylation at CpG islands in the ileum of Gpx1/2-KO mice frequently correlates with loss of H3K27 trimethylation at the same loci. Inflammation-associated DNA methylation occurs preferentially in tissue-specific silent genes and, importantly, is much more frequently represented in tumors than is age-dependent DNA methylation. Sixty percent of aberrant methylation found in tumors is also present in the inflamed tissue. In summary, inflammation creates a signature of aberrant DNA methylation, which is observed later in the malignant tissue and is directed by the PcG complex.
Hahn
Maria A
MA
Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Hahn
Torsten
T
Lee
Dong-Hyun
DH
Esworthy
R Steven
RS
Kim
Byung-Wook
BW
Riggs
Arthur D
AD
Chu
Fong-Fong
FF
Pfeifer
Gerd P
GP
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D004195:Disease Models, Animal; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics; D007079:Ileitis / Q000235:genetics* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000094765:Glutathione Peroxidase GPX1
D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse