# DNA methylation and lncRNA control asynchronous DNA replication at specific imprinted gene domains

## TL;DR

The study shows that DNA methylation and long non-coding RNA control asynchronous DNA replication at specific imprinted gene domains in stem cells.

## Contribution

The paper reveals that DNA methylation and lncRNA regulate allelic replication asynchrony at imprinted gene domains.

## Key findings

- RT asynchrony at Dlk1-Dio3 and Snrpn domains is parent-of-origin dependent and lost during neural differentiation.
- Differential DNA methylation and the lncRNA Meg3 mediate asynchronous replication at the Dlk1-Dio3 domain.
- Replication timing is not linked to TAD organization in the studied imprinted domains.

## Abstract

Besides genome-wide patterns of replication timing (RT), some genes display allelic replication asynchrony in stem cells, brought about by stochastic events and genetic polymorphisms. Whether epigenetic modifications control asynchronous replication remains unclear. Here, we explore domains controlled by genomic imprinting, where parental DNA methylation imprints mediate allele-specific gene expression. Our genome-wide and locus-specific assays in mono-parental and hybrid mouse ESCs reveal pronounced RT asynchrony—which is parent-of-origin dependent and lost upon neural differentiation—at the Dlk1-Dio3 and Snrpn domains, which both comprise lncRNA polycistrons. Generating a range of mutant lines, we find that asynchronous replication at Dlk1-Dio3 is mediated by differential DNA methylation, and that the lncRNA Meg3 controls early replication across parts of the domain on the maternal chromosome. Moreover, we find no evidence that RT and organisation into TADs are linked in this domain. The combined replication timing, DNA methylation, 3D chromatin structure, and gene expression data highlight how parental methylation imprints and lncRNA expression control replication and can override RT domain organisation.

It is not fully understood why genomic loci show asynchronous DNA replication. Here, the authors show that two imprinted gene domains replicate asynchronously between the parental chromosomes due to differential DNA methylation and non-coding RNA, leading to allelic differences.