Expression and DNA methylation of the transgene locus TKZ751 are controlled by genotype-specific modifier genes. The DBAl2 and 129 genetic backgrounds enhanced expression, while the BALBk background suppressed expression, but only following maternal inheritance of the BALB/c modifier. Epigenetic modification of the transgene locus was cumulative over successive generations, which in BALE/c mice resulted in an irreversible methylation after three consecutive germline passages. Therefore, at the TKZ751 locus the germline fails to reverse pieviously acquired epigenetic modifications, a process that is usually essential to restore the genomic totipotency. Hence the genotypespecific modifier genes regulate penetrance and expressivity as well as parental imprinting of the TKZ751 locus through epigenetic modification.