A skeletal muscle-specific mouse lgf2 repressor lies 40 kb downstream of the gene

Igf2 and H19 are closely linked and reciprocally expressed genes on distal chromosome 7 in the mouse. We have previously shown that a 130 kb YAC trans gene contains multiple tissue-specific enhancers for expression of both gen es during embryogenesis. The YAC also contains all the crucial elements res ponsible for initiating and maintaining appropriate parent-of-origin-specif ic expression of these genes at ectopic sites, with expression of Igf2 afte r paternal inheritance and of H19 after maternal inheritance. Located centr ally between Igf2 and H19 are two prominent DNaseI hypersensitive sites, an d two stretches of sequence that are conserved between mouse and human. In this study, we have deleted, from the transgene, a one kb part of the inter genic region that contains the hypersensitive sites and one of the homologo us stretches. We demonstrate that this deletion results in loss of maternal Igf2 repression in skeletal muscle cells, most strikingly in the tongue, l ate in embryogenesis. We propose that the intergenic region functions as a tissue-specific repressor element, forming an integral part of the complex regulatory mechanism that controls monoallelic gene expression in this doma in.