Tissue specific insulator function at H19/Igf2 revealed by deletions at the imprinting control region.

Ideraabdullah FY, Thorvaldsen JL, Myers JA, Bartolomei MS

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/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 1.3kb deletion at the H19/Igf2 ICR [Δ2,3] removing two of four CTCF sites and the intervening sequence, approximately 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 post-translational modifications of the insulator protein CTCF.

Chromatin Shearing

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July, 2014



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