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

• Main Authors: Steine, Eveline J. (Contributor), Ehrich, Mathias (Author), Bell, George W. (Contributor), Raj, Arjun (Contributor), Reddy, Seshamma (Contributor), van Oudenaarden, Alexander (Contributor), Jaenisch, Rudolf (Contributor), Linhart, Heinz G. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Physics (Contributor), Whitehead Institute for Biomedical Research (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: American Society for Clinical Investigation, 2012-09-28T16:18:49Z.
• Subjects: Article
• Online Access: Get fulltext

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.
Prins Bernhard Cultuurfonds (Amsterdam, Netherlands) ("Banning-de Jong Fonds")
Fritz Thyssen-Stiftung
Philip Morris International
National Institutes of Health (U.S.) (NIH Grant RO1-CA087869)
Burroughs Wellcome Fund (Career Award at the Scientific Interface)
National Institutes of Health (U.S.) (Director's Pioneer award)
National Cancer Institute (U.S.) (award U54CA143874)