Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing.
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 Apc Min/+ mice. We found that Dnmt3b1 enhanced the number of colon tumors in Apc Min/+ 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.
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Heinz G
HG
Linhart
Haijiang
H
Lin
Yasuhiro
Y
Yamada
Eva
E
Moran
Eveline J
EJ
Steine
Sumita
S
Gokhale
Grace
G
Lo
Erika
E
Cantu
Mathias
M
Ehrich
Timothy
T
He
Alex
A
Meissner
Rudolf
R
Jaenisch
D000236:Adenoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D020868:Gene Silencing; D017491:Genes, APC; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000097584:DNA Methyltransferase 3B
D002273:Carcinogens; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D007335:Insulin-Like Growth Factor II; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C513121:IGF2 protein, mouse