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Updated: Aug 9, 2026
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Suppression of intestinal neoplasia by deletion of Dnmt3b
Haijiang Lin1, Yasuhiro Yamada, Suzanne Nguyen
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02141, USA.
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.
Insights
Loss of Dnmt3b did not affect early intestinal tumor formation but significantly reduced larger adenoma development. Dnmt3b is crucial for initial tumor growth but not for maintaining established tumors.
Area of Science:
- Oncology
- Epigenetics
- Genetics
Background:
- Aberrant gene silencing via DNA methylation is linked to cancer progression.
- Many tumors exhibit both increased gene silencing and global DNA hypomethylation.
- The role of de novo methylation in early tumor development is not fully understood.
Purpose of the Study:
- To investigate the role of de novo methyltransferase Dnmt3b in intestinal tumor formation.
- To determine if Dnmt3b is essential for the transition from microadenomas to macroscopic adenomas.
- To assess the requirement of Dnmt3b for the maintenance of established colonic tumors.
Main Methods:
- Conditional inactivation of the Dnmt3b gene in Apc(Min/+) mice.
- Analysis of microadenoma and macroscopic adenoma formation in the colon.
- Examination of Dnmt3b expression in different stages of tumor development.
Main Results:
- Loss of Dnmt3b did not impact the formation of intestinal microadenomas.
- A significant reduction in macroscopic colonic adenoma formation was observed in Dnmt3b-deficient mice.
- Regions of Dnmt3b inactivation were found in large adenomas, indicating its role in initial outgrowth.
Conclusions:
- Dnmt3b plays a critical role in the transition from early-stage microadenomas to macroscopic colonic tumors.
- De novo methylation mediated by Dnmt3b is required for the initial outgrowth of macroscopic adenomas.
- Dnmt3b is not essential for the maintenance of established colonic tumor growth after the transition stage.
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