Induction of tumors in mice by genomic hypomethylation.
Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele, which reduces Dnmt1 expression to 10% of wild-type levels and results in substantial genome-wide hypomethylation in all tissues. The mutant mice were runted at birth, and at 4 to 8 months of age they developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability.
Gaudet
François
F
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Hodgson
J Graeme
JG
Eden
Amir
A
Jackson-Grusby
Laurie
L
Dausman
Jessica
J
Gray
Joe W
JW
Leonhardt
Heinrich
H
Jaenisch
Rudolf
R
D000483:Alleles; D000818:Animals; D001724:Birth Weight; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D033481:Chromosomes, Mammalian / Q000235:genetics* / Q000502:physiology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D020077:Endogenous Retroviruses / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D016259:Genes, myc; D006579:Heterozygote; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000502:physiology; D014314:Trisomy; D014775:Virus Activation
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse