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A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing

Abstract

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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Figure 1: Genes showing frequent DNA hypermethylation and frequently silenced in adult cancers remain unmethylated in embryonal carcinoma (EC) and embryonic stem (ES) cells.
Figure 2: EC cells retain a plasticity of expression that is lacking in adult cancer cells.
Figure 3: Genes showing frequent DNA hypermethylation in cancer are marked by 'bivalent' chromatin in ES cells, including the Polycomb group (PcG) protein–associated histone modification, methylated H3K27 (H3K27me).
Figure 4: Genes studied in EC cells share the bivalent chromatin pattern seen in ES cells but add additional repressive marks characteristic of these same genes when DNA demethylation is induced in adult cancers.
Figure 5: Changes in histone modifications and localization of known Polycomb group (PcG) proteins to the gene promoters in Tera-2 cells with ATRA-induced differentiation.
Figure 6: Overexpression of Bmi1 can cause progressive promoter DNA methylation of the SFRP5 gene in EC cells.

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Acknowledgements

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.

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Contributions

J.E.O. and S.B.B. designed this study. J.O., K.M.M., X.Y., K.E.S., H.P.M.,W.C.,V.C.D. and K.P. contributed collaborative experimental results. L.C. and S.G.S. managed the growth and manipulation of ES cells. D.M.B. assisted with characterization of the teratocarcinoma cell explants. D.N.W. and J.G.H. assisted J.E.O. and S.B.B. with data analysis and preparation of the manuscript. L.C. and W.Y. helped with performance and interpretation of microarray results that contributed to the data. T.J. provided antibodies generated in his laboratory for most of the histone modifications studied by ChIP analysis.

Corresponding author

Correspondence to Stephen B Baylin.

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Competing interests

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.

Supplementary information

Supplementary Fig. 1

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)

Supplementary Table 1

Literature references for DNA-hypermethylated genes from Figure 1. (PDF 70 kb)

Supplementary Table 2

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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