Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer

  1. Jean-Pierre J. Issa1,9
  1. 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  2. 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  3. 3 CNRS, UMR 144, Institut Curie, 75248 Cedex 05, Paris, France;
  4. 4 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital and Research Institute, Nagoya 464-8681, Japan;
  5. 5 Division of Molecular Oncology, Aichi Cancer Center Hospital and Research Institute, Nagoya 464-8681, Japan;
  6. 6 Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA;
  7. 7 Genetic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20889, USA;
  8. 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    Abstract

    Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylation-resistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genome-wide analysis showed that 22% of human genes were predicted to be methylation-prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states.

    Footnotes

    • Received March 4, 2010.
    • Accepted July 15, 2010.
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    1. Published in Advance August 17, 2010, doi: 10.1101/gr.107318.110 Genome Res. 20: 1369-1382 Copyright © 2010 by Cold Spring Harbor Laboratory Press

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