Oppositely Imprinted Genes Can Be Controlled by a Single Center

KEY CONCEPTS
- Imprinted genes are controlled by methylation of cisacting sites.
- Methylation may be responsible for either inactivating or activating a gene. 

Imprinting is determined by the state of methylation of a cis-acting site near a target gene or genes. These regulatory sites are known as differentially methylated domains (DMDs) or imprinting control regions (ICRs). Deletion of these sites removes imprinting, and the target loci then behave the same in both maternal and paternal genomes.

The behavior of a region containing the genes Igf2 and H19 illustrates the ways in which methylation can control gene activity. FIGURE 1 shows that these two genes react oppositely to the state of methylation at the ICR located between them. The ICR is methylated on the paternal allele. H19 shows the typical response of inactivation. Note, however, that Igf2 is expressed. The reverse situation is found on a maternal allele, where the ICR is not methylated; H19 now becomes expressed, but Igf2 is inactivated.

FIGURE 1. The ICR is methylated on the paternal allele, where Igf2 is active and H19 is inactive. The ICR is unmethylated on the maternal allele, where Igf2 is inactive and H19 is active. 

The control of Igf2 is exercised by an insulator contained within the ICR (see the Chromatin chapter for a discussion of insulators). FIGURE 2 shows that when the ICR is unmethylated it binds the protein CTCF. This creates a functional insulator that blocks an enhancer from activating the Igf2 promoter. This is an unusual effect in which methylation indirectly activates a gene by blocking an insulator.

FIGURE 2. The ICR contains an insulator that prevents an enhancer from activating Igf2. The insulator functions only when CTCF binds to unmethylated DNA. 

The regulation of H19 shows the more usual direction of control in which methylation creates an inactive imprinted state. This could reflect a direct effect of methylation on promoter activity, though the effect could also be due to additional factors. CTCF regulates chromatin by repressing H3K27 trimethylation at the Igf2 locus independent of repression by DNA hypermethylation. As a result, the effects of CTCF on chromatin, as well as on DNA methylation, likely contribute to the imprinting of H19 and Igf2.