Adult cancers may derive from stem or early progenitor cells1,2. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors3,4,5. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers6,7,8. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.
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Special thanks to L. Meszler (Cell Imaging Core Facility, The Sidney Kimmel Comprehensive Cancer Center), P. Argani (Pathology Department, Johns Hopkins University) and G. Dimri (Northwestern University) for providing the Bmi1cDNA. The pBABE-puro retroviral construct was provided by G. Dimri (Northwestern University). This work was supported by US National Institutes of Health grants CA116160 to S.B.B. and HL073781 to L.C. and National Cancer Institute grant CA043318 to S.B.B.
The commercial rights to the methylation-specific PCR (MSP) technique belong to Oncomethylome. S.B.B and J.G.H. serve as consultants to Oncomethylome and are entitled to royalties from any commercial use of this procedure.
Model for how abnormal DNA methylation may be recruited to most tumor suppressor genes in adult cancer cells, reflecting a stem or progenitor cell of origin. (PDF 122 kb)
Literature references for DNA-hypermethylated genes from Figure 1. (PDF 70 kb)
PCR Primers and conditions. (PDF 31 kb)
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Ohm, J., McGarvey, K., Yu, X. et al. A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39, 237–242 (2007). https://doi.org/10.1038/ng1972
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