Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing
Open Access
- 1 December 2007
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 21 (23), 3110-3122
- https://doi.org/10.1101/gad.1594007
Abstract
Increased methylation of CpG islands and silencing of affected target genes is frequently found in human cancer; however, in vivo the question of causality has only been addressed by loss-of-function studies. To directly evaluate the role and mechanism of de novo methylation in tumor development, we overexpressed the de novo DNA methyltransferases Dnmt3a1 and Dnmt3b1 in ApcMin/+ mice. We found that Dnmt3b1 enhanced the number of colon tumors in ApcMin/+ mice approximately twofold and increased the average size of colonic microadenomas, whereas Dnmt3a1 had no effect. The overexpression of Dnmt3b1 caused loss of imprinting and increased expression of Igf2 as well as methylation and transcriptional silencing of the tumor suppressor genes Sfrp2, Sfrp4, and Sfrp5. Importantly, we found that Dnmt3b1 but not Dnmt3a1 efficiently methylates the same set of genes in tumors and in nontumor tissues, demonstrating that de novo methyltransferases can initiate methylation and silencing of specific genes in phenotypically normal cells. This suggests that DNA methylation patterns in cancer are the result of specific targeting of at least some tumor suppressor genes rather than of random, stochastic methylation followed by clonal selection due to a proliferative advantage caused by tumor suppressor gene silencing.This publication has 69 references indexed in Scilit:
- DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNANature, 2007
- Genome-wide maps of chromatin state in pluripotent and lineage-committed cellsNature, 2007
- Mitotic recombination and uniparental disomy in Beckwith–Wiedemann syndromeGenomics, 2007
- Multistep carcinogenesis of the colon in ApcMin/+ mouseCancer Science, 2006
- Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancerNature Genetics, 2006
- Chromatin immunoprecipitation and microarray-based analysis of protein locationNature Protocols, 2006
- CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2Proceedings of the National Academy of Sciences of the United States of America, 2006
- CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerNature Genetics, 2006
- Control of Developmental Regulators by Polycomb in Human Embryonic Stem CellsCell, 2006
- Polycomb complexes repress developmental regulators in murine embryonic stem cellsNature, 2006