Regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation in colorectal cancer

Authors

  • Guoren Deng,

    Corresponding author
    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
    • Gastrointestinal Research Laboratory, 151M2, Veteran Affairs Medical Center and University of California San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
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    • Fax: +415-750-6972.

  • Anh Nguyen,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Hirofumi Tanaka,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Koji Matsuzaki,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Ian Bell,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Kshama R. Mehta,

    1. Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Jonathan P. Terdiman,

    1. Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Frederic M. Waldman,

    1. Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Sanjay Kakar,

    1. Department of Anatomy Pathology, Veteran Affairs Medical Center and University of California San Francisco, San Francisco, CA, USA
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  • James Gum,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Suzanne Crawley,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Marvin H. Sleisenger,

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Young S. Kim

    1. Gastrointestinal Research Laboratory, Veteran Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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Abstract

Regional DNA hypermethylation and global DNA hypomethylation are 2 epigenetic alterations associated with colorectal cancers. However, their correlation with microsatellite instability (MSI) and chromosomal instability (CIN) in colorectal cancer, and their relationship with chromatin conformation and histone modification are not clear. In this study, we analyzed regional and global methylation in 16 cell lines and 64 primary colorectal cancers. We found that MSI and CIN are 2 alternative events in most cell lines and tumors. Furthermore, regional hypermethylation and global hypomethylation are also alternative events in most cases. We also observed a strong correlation between MSI and regional hypermethylation and between CIN and global hypomethylation. We further analyzed chromatin conformation and histone acetylation in cell lines with CIN or MSI. CIN cancers had open chromatin conformation and enriched histone acetylation in repetitive as well as in gene-specific regions. MSI cancers, on the other hand, had closed chromatin conformation and low levels of histone acetylation. After a MSI cell line was treated with 5-aza-2′-deoxycytidine or trichostatin A, the closed chromatin conformation became open, and histone acetylation was enriched. These observations support our hypothesis that in colorectal cancer, regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation, which might have a causal correlation with MSI and CIN, respectively. © 2006 Wiley-Liss, Inc.

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