Imprinted expression of the H19 and Igf2 loci are 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.
This H19Δ3.8kb-5'H19 knockout allele has a 3.8 kbp deletion encompassing the entire DMD and the 461 bp G-rich repeat element. Mice homozygous for the H19Δ3.8kb-5'H19 knockout allele are viable and fertile, with tissue-specific disruption of imprinted expression of H19 and Igf2.
