Genomic imprinting, the differential expression of autosomal genes based on 
their parent of origin, is observed in all eutherian mammals that have been 
examined. In most instances the genes that are imprinted in one species are 
imprinted in others as well, suggesting that imprinting predated eutherian 
radiation. For example, the RNA-coding H19 gene is repressed upon paternal 
inheritance in all species examined to date. Thus, it is surprising that there 
is remarkably little sequence conservation among the cis-acting DNA regulatory 
elements that are required for imprinting of H19 and the tightly linked Igf2 
gene. The most conserved characteristic in the imprinting control region (ICR) 
is the presence of multiple binding sites for the zinc finger protein CTCF, 
raising the possibility that CTCF binding might be sufficient for the reciprocal 
imprinting of H19 and Igf2. To investigate whether a human H19 transgene, 
harboring seven CTCF sites, is correctly recognized and imprinted in the mouse, 
a 100 kb transgene containing the human H19 gene was introduced into the mouse 
germline. The human transgene was specifically methylated after passage through 
the male germline in a copy number-dependent manner, but the methylation was 
unstable, undergoing progressive loss during development. Consequently, the 
transgene was highly expressed upon both maternal and paternal inheritance. 
These results argue that the signals for both the acquisition and maintenance of 
methylation imprinting are diverging rapidly.