Suppression of Intestinal Neoplasia by Deletion of Dnmt3b

Abstract

Aberrant gene silencing accompanied by DNA methylation is associated with neoplastic progression in many tumors that also show global loss of DNA methylation. Using conditional inactivation of de novo methyltransferase Dnmt3b in Apc^Min/+ mice, we demonstrate that the loss of Dnmt3b has no impact on microadenoma formation, which is considered the earliest stage of intestinal tumor formation. Nevertheless, we observed a significant decrease in the formation of macroscopic colonic adenomas. Interestingly, many large adenomas showed regions with Dnmt3b inactivation, indicating that Dnmt3b is required for initial outgrowth of macroscopic adenomas but is not required for their maintenance. These results support a role for Dnmt3b in the transition stage between microadenoma formation and macroscopic colonic tumor growth and further suggest that Dnmt3b, and by extension de novo methylation, is not required for maintaining tumor growth after this transition stage has occurred.

We thank David Pellman, Konrad Hochedlinger, Caroline Beard, Qiang Chang, Marius Wernig, and Taiping Chen for helpful discussions. We are indebted to all members of the Jaenisch lab for critical comments and in particular to Jessica Dausman, Ruth Flannery, and Dongdong Fu for help with the mouse colony and histological analysis.

H.L. was supported by a fellowship from the Canadian Institutes of Health Research. R.J. received support from the NIH (R37-CA84198, RO1-HD0445022, and RO1-CA87869).