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Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer
Eveline J. Steine, … , Rudolf Jaenisch, Heinz G. Linhart
Eveline J. Steine, … , Rudolf Jaenisch, Heinz G. Linhart
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1748-1752. https://doi.org/10.1172/JCI43169.
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Brief Report Oncology

Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer

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Abstract

Human cancer cells frequently have regions of their DNA hypermethylated, which results in transcriptional silencing of affected genes and promotion of tumor formation. However, it is still unknown whether cancer-associated aberrant DNA methylation is targeted to specific genomic regions, whether this methylation also occurs in noncancerous cells, and whether these epigenetic events are maintained in the absence of the initiating cause. Here we have addressed some of these issues by demonstrating that transgenic expression of DNA methyltransferase 3b (Dnmt3b) in the mouse colon initiates de novo DNA methylation of genes that are similar to genes that become methylated in human colon cancer. This is consistent with the notion that aberrant methylation in cancer may be attributable to targeting of specific sequences by Dnmt3b rather than to random methylation followed by clonal selection. We also showed that Dnmt3b-induced aberrant DNA methylation was maintained in regenerating tissue, even in the absence of continuous Dnmt3b expression. This supports the concept that transient stressors can cause permanent epigenetic changes in somatic stem cells and that these accumulate over the lifetime of an organism in analogy to DNA mutations.

Authors

Eveline J. Steine, Mathias Ehrich, George W. Bell, Arjun Raj, Seshamma Reddy, Alexander van Oudenaarden, Rudolf Jaenisch, Heinz G. Linhart

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Figure 1

DNA methylation analysis of colon tumors and colon epithelial cells with or without Dnmt3b transgene expression.

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DNA methylation analysis of colon tumors and colon epithelial cells with...
4 mo dox, Dnmt3b induction; no dox, no Dnmt3b induction; ES c/c, Dnmt1-deficient ES cells; ES tko, Dnmt1/Dnmt3a/Dnmt3b triple-knockout ES cells; gray, no data. Heat map data were generated by mass array analysis and subjected to sample-based unsupervised hierarchical clustering. (A) Tumors and mucosa samples with Dnmt3b induction showed reproducible de novo DNA methylation of specific genomic loci. Imprinted regions (Nespas-, Peg3-, and H19-DMR) were partially methylated; ES tko and ES c/c cells showed loss of DNA methylation. (B) Pairwise correlation of methylation data confirmed similar de novo methylation in all samples with Dnmt3b induction (r, 0.76–0.97; mean r, 0.90). (C) Dnmt3b-mediated DNA methylation in colon mucosa of APC WT mice closely resembled de novo methylation reported for human colon cancer (Supplemental Table 1), which suggests that Dnmt3b can induce cancer-specific de novo methylation in normal cells (red, methylated; blue, unmethylated; black, control/imprinted regions).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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