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.
DNA replication is a complex process that is tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Oncogene expression triggers replicative stress that can lead to genetic instability, driving cancer progression. Thus, revealing the molecular basis for oncogene-induced replication stress is important for understanding of oncogenesis. Here we show that the activation of mutated HRAS leads to a non-canonical replication stress characterized by accelerated replication rate, inducing DNA damage. Mutated HRAS increases topoisomerase 1 (TOP1) expression, which leads to reduced levels of RNA-DNA hybrids (R-loops), driving fork acceleration and damage formation. Restoration of the perturbed replication either by restoration of TOP1 levels or directly by mild replication inhibition results in a dramatic reduction in DNA damage. The findings highlight the importance of TOP1 equilibrium in the regulation of R-loop homeostasis to ensure faithful DNA replication and genome integrity that when dysregulated can be a mechanism of oncogene-induced DNA damage.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.