Chromosome loops, insulators, and histone methylation: New insights into regulation of imprinting in clusters

Imprinted genes in mammals are organized into clustersin which genes share regulatory elements. Igf2 and H19are separated by 100 kb (kilobases) of DNA, and bothgenes use enhancers that are located distal to H19. Alternate access to the enhancers by the two genes is in partregulated by a CTCF-dependent insulator located upstream of H19. We find that differentially methylated regions in both genes interact physically over the 100-kbdistance. These interactions are epigenetically regulatedand partition maternal and paternal chromatin into distinctloops. This creates a simple epigenetic switch for Igf2whereby it moves between an active and a silent chromatin domain. In the adjacent Kcnq1ot1 cluster, by contrast, a noncoding RNA gene is flanked by several silentgenes, which are marked by repressive histone modifications. Histone methylation is targeted directly or indirectlyto the region by the noncoding RNA and is maintained inthe absence of DNA methylation. We propose that imprinting regulation in clusters falls into different categories. The “insulator-loop” model may also be applicableto Dlk1/Gtl2 and Rasgrf1. The “noncoding RNA” modelis likely to be applicable to Igf2r/Air, to imprinted X-inactivation, and to other maternally imprinted loci