| DNA methylation and histone modifications are two key regulators of epigenetics within the cell. Both are important in regulating gene expression and nuclear architecture. DNA methylation, or the addition of a methyl group to a cytosine which is part of a 5'-CpG-3' dinucleotide, is carried out by the DNA methyltransferase enzymes, or DNMTs. DNA methylation plays an important role in a variety of normal cellular processes, including stem cell differentiation, embryonic development, genomic imprinting, and X-chromosome inactivation. The DNMTs are essential for normal development, as a variety of Dnmt-deficient mouse models have been developed and demonstrate embryonic lethality, developmental defects, and alterations in DNA methylation patterns.;Cancer cells have an abnormal distribution of DNA methylation as compared to normal cells, but the mechanism by which these abnormal DNA methylation patterns is established and maintained is not well understood. Cancer cells express aberrant DNMT3B transcripts, which encode truncated proteins. One of these commonly expressed transcripts, DNMT3B7, has been shown to alter DNA methylation patterns of particular genes when expressed in 293 cells. In this in vitro system, some genes become hypomethylated, whereas others become hypermethylated, which is reminiscent of what is observed in many human cancers.;To test if a truncated DNMT3B isoform could disrupt DNA methylation in vivo, two lines of DNMT3B7 transgenic mice were generated. DNMT3B7 transgenic mice display craniofacial abnormalities, cardiac defects, and skeletal defects, similar to abnormalities observed in Dnmt3b-/- mice, suggesting that DNMT3B7 interferes with the function of Dnmt3b. DNMT3B7 transgenic mice have only subtle changes in DNA methylation in transgeneexpressing organs, and rarely develop cancer.;However, when DNMT3B7 is expressed in the Emu-Myc mouse tumor model, which develops B cell lymphoma, dramatic effects on tumorigenesis are observed. Emu-Myc/DNMT3B7 transgenic mice develop mediastinal lymphomas with increased frequency. Emu-Myc/DNMT3B7 tumors have increased chromosomal instability, as well as increased global methylation levels and more locus-specific perturbations in DNA methylation patterns compared to Emu-Myc lymphomas. This work represents the first in vivo modeling of cancer-associated DNA methylation changes and suggests that truncated DNMT3B isoforms contribute to the redistribution of DNA methylation characterizing many human tumors. |
