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Common Altered Epigenomic Domains in Cancer Cells: Characterization and Subtle Variations
Institute of Molecular Biology and Biochemistry, National Yang Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan
VGH-YM Genome Center, National Yang Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan
Institute of Biomedical Informatics, National Yang Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan
These authors contribute equally to this work.
* Author to whom correspondence should be addressed.
Received: 9 February 2011; in revised form: 22 March 2011 / Accepted: 1 April 2011 / Published: 18 April 2011
Abstract: We have previously identified large megabase-sized hypomethylated zones in the genome of the breast cancer cell line MCF-7 using the TspRI-ExoIII technique. In this report, we used a more convenient high throughput method for mapping the hypomethylated zones in a number of human tumor genomes simultaneously. The method was validated by the bisulfite sequencing of 39 randomly chosen sites in a demethylated domain and by bisulfite genome-wide sequencing of the MCF-7 genome. This showed that the genomes of the various tumor cell lines, as well as some primary tumors, exhibit common hypomethylated domains. Interestingly, these hypomethylated domains are correlated with low CpG density distribution genome-wide, together with the histone H3K27Me3 landscape. Furthermore, they are inversely correlated with the H3K9Ac landscape and gene expression as measured in MCF-7 cells. Treatment with drugs resulted in en-bloc changes to the methylation domains. A close examination of the methylation domains found differences between non-invasive and invasive tumors with respect to tumorigenesis related genes. Taken together these results suggest that the human genome is organized in epigenomic domains that contain various different types of genes and imply that there are cis- and trans-regulators that control these domain-wide epigenetic changes and hence gene expression in the human genome. The hypomethylated domains are located in gene deserts that contain mainly tissue-specific genes and therefore we hypothesize that tumor cells keep these regions demethylated and silenced in order to save energy and resources and allow higher levels of cell proliferation and better survival (a thrifty tumor genome hypothesis).
Keywords: epigenetic; DNA methylation; histone modification; cancer
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Tsai, Y.-C.; Chiao, C.-H.; Chang, I.-F.; Chen, D.-T.; Liu, T.-T.; Hua, K.; Chang, C.-H.; Hsu, M.-T. Common Altered Epigenomic Domains in Cancer Cells: Characterization and Subtle Variations. Cancers 2011, 3, 1996-2013.
Tsai Y-C, Chiao C-H, Chang I-F, Chen D-T, Liu T-T, Hua K, Chang C-H, Hsu M-T. Common Altered Epigenomic Domains in Cancer Cells: Characterization and Subtle Variations. Cancers. 2011; 3(2):1996-2013.
Tsai, Yi-Chien; Chiao, Chun-Hui; Chang, Ian Yi-Feng; Chen, Dow-Tien; Liu, Tze-Tze; Hua, Kate; Chang, Chuan-Hsiung; Hsu, Ming-Ta. 2011. "Common Altered Epigenomic Domains in Cancer Cells: Characterization and Subtle Variations." Cancers 3, no. 2: 1996-2013.