Parent-of-origin-specific expression at imprinted genes is regulated by 
allele-specific DNA methylation at imprinting control regions (ICRs). This 
mechanism of gene regulation, where one element controls allelic expression of 
multiple genes, is not fully understood. Furthermore, the mechanism of gene 
dysregulation through ICR epimutations, such as loss or gain of DNA methylation, 
remains a mystery. We have used genetic mouse models to dissect ICR-mediated 
genetic and epigenetic regulation of imprinted gene expression. The 
H19/insulin-like growth factor 2 (Igf2) ICR has a multifunctional role including 
insulation, activation and repression. Microdeletions at the human H19/IGF2 ICR 
(IC1) are proposed to be responsible for IC1 epimutations associated with 
imprinting disorders such as Beckwith-Wiedemann syndrome (BWS). Here, we have 
generated and characterized a mouse model that mimics BWS microdeletions to 
define the role of the deleted sequence in establishing and maintaining 
epigenetic marks and imprinted expression at the H19/IGF2 locus. These mice 
carry a 1.3 kb deletion at the H19/Igf2 ICR [Δ2,3] removing two of four 
CCCTC-binding factor (CTCF) sites and the intervening sequence, ∼75% of the ICR. 
Surprisingly, the Δ2,3 deletion does not perturb DNA methylation at the ICR; 
however, it does disrupt imprinted expression. While repressive functions of the 
ICR are compromised by the deletion regardless of tissue type, insulator 
function is only disrupted in tissues of mesodermal origin where a significant 
amount of CTCF is poly(ADP-ribosyl)ated. These findings suggest that insulator 
activity of the H19/Igf2 ICR varies by cell type and may depend on cell-specific 
enhancers as well as posttranslational modifications of the insulator protein 
CTCF.