Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity

Abstract

The insulin-like growth factor 2 gene (Igf2) is imprinted in most somatic tissues of the mouse with the exception of the choroid plexus and leptomeninges of the brain, where it is expressed from both alleles. The imprinting of Igf2 is dependent upon an imprinting control region (ICR) that lies 90 kb 3' of the gene and acts as a chromatin insulator to block enhancers that lie further 3' on the chromosome. Based on this model we would expect that enhancers of brain-specific expression of Igf2 would lie 5' of the ICR, and thus be insensitive to its action. Here we describe a 12 kb deletion of a region 5' of the ICR that is hypersensitive to nuclease digestion in chromatin. Its deletion results in a biallelic decrease in expression of Igf2, but not H19, in the brain, consistent with the proposal that it encodes a positive regulatory element. In addition, the deletion results in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue. Lastly, the reduction in IGFII expression in the adult is accompanied by increased fat deposition and occasional obesity. Overweight animals are hypophagic, suggesting that IGFII affects fat metabolism rather than feeding behavior in adult mice.