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DNA methylation and lncRNA expression control asynchronous DNA replication at imprinted gene domains

ABSTRACT: Eukaryotic genomes are structured in zones that replicate predominantly early or late. Besides these genome-wide patterns of replication timing (RT), some genes display asynchronous replication between the two alleles in certain stem cells, brought about by stochastic processes and genetic polymorphisms. To what extent epigenetic modifications control asynchronous replication remains unclear. As a paradigm to address this question we explored imprinted chromosomal domains, at which parental DNA methylation imprints mediate parental allele-specific gene expression. Our genome-wide and locus-specific RT assays in mono-parental and hybrid mouse embryonic stem cells (mESCs) reveal a pronounced replication asynchrony between the parental chromosomes at the Dlk1-Dio3 and Snrpn domains. This asynchrony is strictly parent-of-origin dependent. By generating a range of mutant mESC lines, we find that the replication asynchrony at Dlk1-Dio3 is mediated by parental allele-specific methylation at DMRs (Differentially Methylated Regions). Moreover, lncRNA polycistron expression controls early replication across parts of the domain on the maternal chromosome. As a result, at these imprinted domains, RT domains become unlinked from 3D chromatin architecture as assayed by Hi-C. Our combined data highlight how parental DNA methylation imprints and lncRNA expression can locally be used to override intrinsic RT domain organization.

ORGANISM(S): Mus musculus

PROVIDER: GSE287936 | GEO | 2025/12/13

REPOSITORIES: GEO

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