LOCATION OF ENHANCERS IS ESSENTIAL FOR THE IMPRINTING OF H19 AND IGF2GENES

Genomic imprinting is the process in mammals by which gamete-specific epigenetic modifications establish the differential expression of the two alleles of a gene, The tightly linked H19 and Igf2 genes are expre ssed in tissues of endodermal and mesodermal origin, with H19 expresse d from the maternal chromosome and Igf2 expressed from the paternal ch romosome, A model has been proposed to explain the reciprocal imprinti ng of these genes(1); in this model, expression of the genes is govern ed by competition between their promoters for a common set of enhancer s. An extra set of enhancers might be predicted to relieve the competi tion, thereby eliminating imprinting, Here we tested this prediction b y generating mice with a duplication of the endoderm-specific enhancer s, The normally silent Igf2 gene on the maternal chromosome was expres sed in liver, consistent with relief from competition. We then generat ed a maternal chromosome containing a single set of enhancers located equidistant from Igf2 and H19; the direction of the imprint was revers ed, Thus, the location of the enhancers determines the outcome of comp etition in liver, and the strength of the H19 promoter is not sufficie nt to silence Igf2.