Imprinting of Igf2r: Sense and Antisense Competition Model (Fig. 1)
An elegant model of sense/antisense competition has been proposed by Wutz et al. (1997). On the mouse paternal allele, the IC in region 2 is unmethylated, while promoter region 1 is methylated; antisense Air is transcribed. Aircompetes and turns off the Igf2r sense transcript. On the maternal allele, the IC is methylated and Air is turned off. Promoter region 1 is unmethylated, and Igf2r is transcribed. Two cis-regulatory elements in region 2, the de novo methylation signal (DNS) and the allele-discrimination signal (ADS), have been shown to be involved in the establishment of differential methylation of the Igf2r DMR (Birger et al. 1999). Imprinting of Igf2r is tissue specific. In the mouse central nervous system (CNS), Igf2r is transcribed from both parental alleles (Wang et al. 1994). On the paternal allele, the IC is unmethylated, and Air is transcribed. The promoter region 1 is unmethylated; Air transcription fails to outcompete Igf2r on the paternal allele (Hu et al. 1999). Imprinting of Igf2r is species specific. In humans, the “homologous IC” is methylated on the maternal allele. On the paternal allele, unmethylated IC fails to initiate antisense transcript (T.H. Vu and A.R. Hoffman, unpubl.). The human homologous IC is inactive. Promoter region 1 is unmethylated on both alleles;IGF2R is not imprinted. We propose that the active IC in the mouse coordinates the correct methylation pattern in promoter region 1 and initiates antisense transcription. In mouse CNS, IC fails to establish the correct promoter methylation, while in humans the “defunct IC” fails in both activities. Imprinting ofIgf2r is also observed in marsupials (mammals that give birth to altricial offspring) but this imprinting is not observed in monotremes (egg-laying mammals) (John et al. 2000; Killian et al. 2000). However, no differential methylation is detected in region 2 of the marsupial Igf2r. The mechanism of marsupialIgf2r imprinting remains to be explored. Since the discovery of Air, imprinted antisense transcripts are observed in all four major imprinting models (see text). In humanKVLQT1, targeted deletion of the LIT1 CpG island (the putative IC) abolishes transcription of the antisense on the paternal allele, accompanied by activation of multiple normally suppressed paternal alleles in the KVLTQ region (Horike et al. 2000).
