Letter | Published:

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

Nature Genetics volume 39, pages 237242 (2007) | Download Citation

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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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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.

Author information

Affiliations

  1. Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • Joyce E Ohm
    • , Kelly M McGarvey
    • , Kornel E Schuebel
    • , Helai P Mohammad
    • , Wei Chen
    • , Vincent C Daniel
    • , Wayne Yu
    • , Kevin Pruitt
    • , Saul J Sharkis
    • , D Neil Watkins
    • , James G Herman
    •  & Stephen B Baylin
  2. Program in Cellular and Molecular Medicine, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • Kelly M McGarvey
    • , Linzhao Cheng
    • , Saul J Sharkis
    • , James G Herman
    •  & Stephen B Baylin
  3. Institute for Cell Engineering, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • Xiaobing Yu
    •  & Linzhao Cheng
  4. Biometry and Clinical Trials Division, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • Linzhao Cheng
    •  & Leslie Cope
  5. Program in Human Genetics and Molecular Biology, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • Wei Chen
  6. Pathology Department, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA.

    • David M Berman
  7. Research Institute of Molecular Pathology, The Vienna Biocenter, Dr. Bohrgasse 7, A-1030, Vienna, Austria.

    • Thomas Jenuwein

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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.

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.

Corresponding author

Correspondence to Stephen B Baylin.

Supplementary information

PDF files

  1. 1.

    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.

  2. 2.

    Supplementary Table 1

    Literature references for DNA-hypermethylated genes from Figure 1.

  3. 3.

    Supplementary Table 2

    PCR Primers and conditions.

About this article

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DOI

https://doi.org/10.1038/ng1972

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