Imprinted expression of the H19 and Igf2 loci is dependent upon a differentially methylated domain (DMD or Rr27) that coordinates the reciprocal maternal/paternal expression of H19 and Igf2 by controlling access to shared enhancers. Specifically, on the maternal allele, the DMD acts as a methylation-sensitive insulator that results in H19 expression and Igf2 inactivation. The four CpG-rich regions in the DMD bind CCCTC-binding factor (CTCF) on the hypomethylated maternal allele, subsequently blocking the Igf2 gene from the enhancers shared by H19 and Igf2. On the paternal allele, the hypermethylation of DMD concomitantly methylates H19, resulting in H19 inactivation and Igf2 expression. The DMRflox mice have loxP sites flanking the H19/Igf2 imprinting control region, at -6.5 to -0.8kb upstream of the H19 major start site. Mice homozygous for the DMRflox allele are viable and fertile. After Cre recombinase-deletion of the floxed DMD region, the resulting mice exhibit tissue-specific disruption of imprinted expression of H19 and Igf2. The donating laboratory notes that upon Cre-mediated recombination on the maternal chromosome there is a phenotype that mimics Beckwith Wiedemann syndrome. Maternal Igf2 expression is activated so that overall there is 2X expression of Igf2 and maternal H19 expression is reduced by 4-50-fold in a tissue dependent manner. Together, these expression changes result in a series of phenotypes including fetal overgrowth, cancer susceptibility, and cardiac insufficiency in aged mice. These DMRflox mice may be useful for studying the chromatin interactions and epigenetics involved in H19/Igf2 imprinting.

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The DMRflox allele allows cre-mediated deletion of a 5.7kbp region, containing the differentially methylated domain (DMD or Rr27), upstream of the H19 start site. This DMD coordinates the reciprocal expression of H19 and Igf2 by controlling access to shared enhancers. These mice may be used to generate temporal and tissue-specific deletions of this imprinting control region for studying the chromatin interactions and epigenetics involved in H19/Igf2 imprinting.

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