Role of the Tgkd Transgene in the Development of Ovarian Teratomas.

BALAKRISHNAN, A; CIRIO, MC; CHAILLET, JR

Congreso; Society for the Study of Reproduction (SSR); 2009

Epigenetic changes in the genome have profound effects on mammaliandevelopment and disease. FVB-Tgkd is a mouse strain that demonstratesthe effect of aberrant methylation in female germ cells. TheFVB-Tgkd strain carries the genomically imprinted Tgkd transgenein an FVB/N (FVB) strain background. In all somatic cells ofFVB-Tgkd mice, the maternal Tgkd allele is methylated and thepaternal Tgkd allele is unmethylated. The maternal methylationis established during oogenesis, and is then inherited (maintained)by the embryo. Homozygous carriers of FVB-Tgkd die during embryonicdevelopment. Hemizygous carriers survive, although approximately17% of the hemizygous female carriers develop ovarian teratomas(OTs). OTs are tumors derived from non-ovulated oocytes inthe ovary. Tgkd is inserted in a 200-kb region of chromosome8 between the inositol polyphosphate-4-phosphatase (Inpp4b)and interleukin 15 (Il15) genes. The OT phenotype in the FVB-Tgkdstrain was found to be dependent on the site of integrationand also specific to the FVB strain. The strain specificityto the FVB strain is largely due to the strong influence ofa strain-specific modifier locus on chromosome 6. Another interestingfeature of this model is the epigenetic origin of the OTs. The methylation of Tgkd appears to be essential for the OT phenotype,as FVB-Tgkd mice deficient in the DNMT3a accessory protein DNMT3Ldid not develop OTs. Furthermore, bisulfite genomic sequencinganalysis confirmed that Tgkd was methylated in FVB-Tgkd oocytesand in OTs from FVB-Tgkd mice, but not in oocytes of homozygousDnmt3L-null FVB-Tgkd mice. Our overall goal is to determinehow the presence of the Tgkd transgene predisposes the FVB femalesto develop OTs. We hypothesize that the Tgkd insertion, throughan epigenetic effect, alters the transcript levels of one ormore of the surrounding genes in the oocyte. This alteration,in the context of a genetic background of homozygous FVB strain-specificmodifier alleles on chromosome 6, causes a proportion of oocytesto undergo parthenogenetic activation and develops into OTs.