Enhancer-dependent, locus-wide regulation of the imprinted mouse insulin-like growth factor II gene

The mouse insulin-like growth factor II (IGF-II) gene is subject to parental imprinting and is predominantly expressed from the paternal chromosome. This allele-specific expression is modified further by cell type, developmental stage, and growth conditions. We show that the ratio of the three major IGF-II mRNAs, each produced from a distinct promoter, is consistent in a variety of tissues and cells representing different modes and phases of the complex regulation. Nuclear run-on assays show that the major changes in total IGF-II mRNA level occur at the level of transcription. Moreover, a targeted disruption of the endoderm-specific enhancers, located 90 kb away from the gene, affects all promoters. The dependency of the promoters on distal enhancers is also shown by transgenesis experiments. Our findings suggest that enhancer-dependent, locus-wide mechanisms play a major role in the coordinate regulation of the multiple IGF-II promoters.