Fig. 6. (A,B) Model of proposed functional interaction of the HUC sequences with Igf2 and H19. Activation of gene expression is represented by (+), repression is represented by (–) and inhibition of enhancer function is indicated by a vertical bar. H19 and Igf2 expression in some tissues is controlled by enhancers located downstream of H19 (green circles) (Leighton et al., 1995; Ishihara et al., 2000). On the maternal allele (MAT), the enhancers have access to the H19 promoter but are prevented from activating Igf2 by the boundary function present in the unmethylated ICR (open red ellipse), mediated by CTCF. On the paternal allele (PAT), the ICR is methylated (closed red ellipse), acting to silence H19 (Drewell et al., 2000). The absence of the boundary means the downstream enhancers are free to activate Igf2. In a subset of mesodermal tissues, expression is controlled by the HUC enhancers located upstream of H19 (yellow circles). On the maternal allele, interaction of the HUCs with the H19 promoter may be mediated by a tethering activity within the unmethylated ICR (open red ellipse). Expression of Igf2 by the HUC enhancers in mesodermal tissues is prevented by the unmethylated tissue-specific silencer element located at the Igf2 DMR1 (open blue diamond) (Constancia et al., 2000). On the paternal allele, the HUCs are free to activate expression of Igf2 while H19 is silenced as before.
