IGF2
H19 and IGF2 expression are closely linked, as they are expressed in the same tissues during fetal development, albeit from differing parental alleles.
This coupled expression is only lost in cases of loss of imprinting (inherited CpG methylated) or promoter mutation.
The hypermethylation of the H19 promoter on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2. In DNMT-null mice, the paternal allele of IGF2 is also silenced as the paternal H19 promoter is no longer methylated and repressed. A reason for the close coupling of H19 and IGF2 expression may be that they share the same 3’ gene enhancer. When this 3’ enhancer was deleted, researchers Leighton et al. found decreased H19 and IGF2 RNA expressions in the gut, liver and kidney; however, the methylation status of these genes were not affected by the deleted enhancer. Suggestions for why H19 is preferentially activated by the 3’ enhancer instead of IGF2 are that H19 has a stronger promoter than IGF2 and that the H19 gene is physically closer to the 3’ enhancers than the IGF2 gene.
It is of interest to note that mice inheriting a deleted maternal H19 and a deleted paternal IGF2 gene were indistinguishable from wildtype mice in birth weight and postnatal growth. Mice inheriting only a deleted maternal H19 gene, however, displayed somatic overgrowth while mice inheriting only a deleted paternal IGF2 gene displayed somatic undergrowth when compared to wildtype mice. This indicates that the loss of H19 is not lethal, H19 expression governs IGF2 repression, and the overexpression of IGF2 is responsible for the overgrowth phenotype observed in the maternal inheritance of a deleted H19 gene.
Read more about this topic: H19 (gene)