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Common altered epigenomic domains in cancer cells: characterization and subtle variations.

Tsai YC, Chiao CH, Chang IY, Chen DT, Liu TT, Hua K, Chang CH, Hsu MT - Cancers (Basel) (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, National Yang Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan. mth@ym.edu.tw.

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).

No MeSH data available.


Related in: MedlinePlus

An example of a highly expressed gene with promoter hypomethylation and gene body hypermethylation. Top panel is the gene map of PTGES3 with the expression number in parenthesis. The lower panel is the level of methylation as determined by bisulfite sequencing; the transcription is from right to left.
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f6-cancers-03-01996: An example of a highly expressed gene with promoter hypomethylation and gene body hypermethylation. Top panel is the gene map of PTGES3 with the expression number in parenthesis. The lower panel is the level of methylation as determined by bisulfite sequencing; the transcription is from right to left.

Mentions: We compared the epigenetic modifications identified in this study with the gene expression patterns obtained from an Affymetric analysis of MCF-7 cells and found that actively expressed genes were associated with promoter demethylation and intragenic methylation (see Figure 6 for example). H3K9Ac was also associated with active expression (Figure 7a), whereas H3K27Me3 was correlated with low gene expression (Figure 7b). Upon close examination we found that the majority of transcribed genes have H3K9Ac only in the 5′ region, whereas very highly expressed genes, such as ribosomal protein genes, have H3K9Ac in both their promoter and intragenic regions. In contrast, silenced genes were associated with promoter methylation, intragenic demethylation and the presence of H3K27Me3. An analysis of the silenced genes associated with H3K27Me3 showed that they are highly enriched for brain, immune and developmentally regulated genes (Figure 8).


Common altered epigenomic domains in cancer cells: characterization and subtle variations.

Tsai YC, Chiao CH, Chang IY, Chen DT, Liu TT, Hua K, Chang CH, Hsu MT - Cancers (Basel) (2011)

An example of a highly expressed gene with promoter hypomethylation and gene body hypermethylation. Top panel is the gene map of PTGES3 with the expression number in parenthesis. The lower panel is the level of methylation as determined by bisulfite sequencing; the transcription is from right to left.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757401&req=5

f6-cancers-03-01996: An example of a highly expressed gene with promoter hypomethylation and gene body hypermethylation. Top panel is the gene map of PTGES3 with the expression number in parenthesis. The lower panel is the level of methylation as determined by bisulfite sequencing; the transcription is from right to left.
Mentions: We compared the epigenetic modifications identified in this study with the gene expression patterns obtained from an Affymetric analysis of MCF-7 cells and found that actively expressed genes were associated with promoter demethylation and intragenic methylation (see Figure 6 for example). H3K9Ac was also associated with active expression (Figure 7a), whereas H3K27Me3 was correlated with low gene expression (Figure 7b). Upon close examination we found that the majority of transcribed genes have H3K9Ac only in the 5′ region, whereas very highly expressed genes, such as ribosomal protein genes, have H3K9Ac in both their promoter and intragenic regions. In contrast, silenced genes were associated with promoter methylation, intragenic demethylation and the presence of H3K27Me3. An analysis of the silenced genes associated with H3K27Me3 showed that they are highly enriched for brain, immune and developmentally regulated genes (Figure 8).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology and Biochemistry, National Yang Ming University, No.155, Sec.2, Linong Street, Taipei, 112 Taiwan. mth@ym.edu.tw.

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).

No MeSH data available.


Related in: MedlinePlus