Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops

Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications(1-5). The paternally expressed gene insulin-like growth-factor 2 (Igf2) is separated by similar to100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries(6-9), silencers(10,11) and activators(12) and regulate the reciprocal expression of the two genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers(13-15). Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains(16-19). Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are epigenetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain.