The 3′ portion of the mouse H19 Imprinting-Control Region is required for proper tissue-specific expression of the Igf2 gene

Genomic imprinting at the H19/Igf2 locus is governed by a cis-acting Imprinting-Control Region (ICR), located 2 kb upstream of the H19 gene. This region possesses an insulator function which is activated on the unmethylated maternal allele through the binding of the CTCF factor. It has been previously reported that paternal transmission of the H19(SilK) deletion, which removes the 3′ portion of H19 ICR, leads to the loss of H19 imprinting. Here we show that, in the liver, this reactivation of the paternal H19 gene is concomitant to a dramatic decrease in Igf2 mRNA levels. This deletion alters higher-order chromatin architecture, Igf2 promoter usage and tissue-specific expression. Therefore, when methylated, the 3′ portion of the H19 ICR is a bi-functional regulatory element involved not only in H19 imprinting but also in ‘formatting’ the higher-order chromatin structure for proper tissue-specific expression of both H19 and Igf2 genes.