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 pa rental imprinting and is predominantly expressed from the paternal chr omosome, This allele-specific expression is modified further by cell t ype, developmental stage, and growth conditions. We show that the rati o Of the three major IGF-II mRNAs, each produced from a distinct promo ter, is consistent in a variety of tissues and cells representing diff erent modes and phases of the complex regulation, Nuclear run-on assay s show that the major changes in total IGF-II: mRNA level occur at. th e level of transcription. Moreover, a targeted disruption of the endod erm-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.