MULTIPLE IMPRINTED SENSE AND ANTISENSE TRANSCRIPTS, DIFFERENTIAL METHYLATION AND TANDEM REPEATS IN A PUTATIVE IMPRINTING CONTROL REGION UPSTREAM OF MOUSE IGF2

The mouse insulin-like growth factor 2 (Igf2) locus is a complex genom ic region that produces multiple transcripts from alternative promoter s, Expression at this locus is regulated by parental imprinting, Howev er, despite the existence of putative imprinting control elements in t he Igf2 upstream region, imprinted transcriptional repression is aboli shed by null mutations at the linked H19 locus, To clarify the extent to which the Igf2 upstream region contains autonomous imprinting contr ol elements we have performed functional and comparative analyses of t he region in the mouse and human, Here we report the existence of mult iple, overlapping imprinted (maternally repressed) sense and antisense transcripts that are associated with a tandem repeat in the mouse Igf 2 upstream region, Regions flanking the repeat exhibit tissue-specific parental allelic methylation patterns, suggesting the existence of ti ssue-specific control elements in the upstream region, Studies in H19 null mice indicate that both parental allelic methylation and monoalle lic expression of the upstream transcripts depends on an intact H19 ge ne acting in cis, The homologous region in human IGF2 is structurally conserved, with the significant exception that it does not contain a t andem repeat. Our results support the proposal that tandem repeats act to target methylation to imprinted genetic loci.