Balanced gene dosage control rather than parental origin underpins genomic imprinting

Mammalian parental imprinting represents an exquisite form of epigenetic control regulating the parent-specific monoallelic expression of genes in clusters. While imprinting perturbations are widely associated with developmental abnormalities, the intricate regional interplay between imprinted genes makes interpreting the contribution of gene dosage effects to phenotypes a challenging task. Using mouse models with distinct deletions in an intergenic region controlling imprinting across the Dlk1-Dio3 domain, we link changes in genetic and epigenetic states to allelic-expression and phenotypic outcome in vivo. This determined how hierarchical interactions between regulatory elements orchestrate robust parent-specific expression, with implications for non-imprinted gene regulation. Strikingly, flipping imprinting on the parental chromosomes by crossing genotypes of complete and partial intergenic element deletions rescues the lethality of each deletion on its own. Our work indicates that parental origin of an epigenetic state is irrelevant as long as appropriate balanced gene expression is established and maintained at imprinted loci. Here the authors investigate whether for imprinted genes the parent-of-origin of the expressed allele or rather appropriate gene dosage is more important for normal development. Using the differentially methylated region of Dlk1-Dio3 gene involved in imprinting, they show that correct parent-of-origin imprinting pattern is secondary to balanced gene dosage.

Automated summary

This study investigates the impact of parental imprinting on gene expression and phenotypic outcomes, and reveals that the parental origin of the epigenetic state is less important than balanced gene dosage for normal development.