Blue boxes represent paternally expressed alleles, red boxes maternally expressed alleles, black boxes silenced alleles, and grey boxes nonimprinted genes. Arrows on boxes indicate transcriptional orientation.
(A) The enhancer–blocker model (also known as the boundary model) is well studied at the Igf2/H19 locus and consists of an ICR located between a pair of reciprocally expressed genes that controls access to shared enhancer elements [,]. On the paternal allele, the differentially methylated domain (DMD) acquires methylation (black circles) during spermatogenesis, which leads to repression of the H19 promoter []. The hypomethylated maternal DMD acts as an insulator element, mediated through binding sites for the methylation-sensitive boundary factor CTCF (shaded ellipse). When CTCF is bound, Igf2 promoter access to the enhancers (E) distal to H19 is blocked.
(B) At the Igf2r locus on Chromosome 17, the paternally expressed, noncoding RNA Air acts to induce bidirectional cis-mediated silencing (black curved lines) on neighbouring protein-coding genes (maternally expressed Igf2r, Slc22a3, and Slc22a2) []. The grey ellipses are the intronic imprint control elements that are maternally methylated (black circles) and contain the promoter of the Air RNA.
(C) At microimprinted domains, oocyte-derived methylation in the promoter region of a protein-coding gene is likely to be the primary epigenetic mark leading to monoallelic silencing. With the exception of the U2af1-rs1 locus, the multiexonic genes within which the paternally expressed transcripts are embedded, escape imprinting (). The paternally expressed Nap1l5 is situated within intron 22 of Herc3, which is expressed from both alleles.