Suppression of intestinal neoplasia by deletion of Dnmt3b.
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.
Lin
Haijiang
H
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02141, USA.
Yamada
Yasuhiro
Y
Nguyen
Suzanne
S
Linhart
Heinz
H
Jackson-Grusby
Laurie
L
Meissner
Alexander
A
Meletis
Konstantinos
K
Lo
Grace
G
Jaenisch
Rudolf
R
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D004273:DNA, Neoplasm; D000097584:DNA Methyltransferase 3B