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DNA methylation and lncRNA expression control asynchronous DNA replication at specific imprinted gene domains [RNA-seq]

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. We explored mammalian imprinted domains, 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. RT thereby becomes unlinked from 3D chromatin architecture as assayed by Hi-C. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE306487 | GEO | 2025/12/12

REPOSITORIES: GEO

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DNA methylation and lncRNA expression control asynchronous DNA replication at specific imprinted gene domains [Hi-C]

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The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation

Project description:The imprinted Dlk1-Dio3 domain comprises the developmental genes Dlk1 and Rtl1, which are silenced on the maternal chromosome in different cell types. On this parental chromosome, the domain’s imprinting control region activates a polycistron that produces the lncRNA Meg3 and many miRNAs (Mirg) and C/D-box snoRNAs (Rian). Although Meg3 lncRNA is nuclear and associates with the maternal chromosome, it is unknown whether it controls gene repression in cis. We created mouse embryonic stem cells (mESCs) that carry an ectopic poly(A) signal, reducing RNA levels along the polycistron, and generated Rian-/- mESCs as well. Upon ESC differentiation, we found that Meg3 lncRNA (but not Rian) is required for Dlk1 repression on the maternal chromosome. Biallelic Meg3 expression acquired through CRISPR-mediated demethylation of the paternal Meg3 promoter led to biallelic Dlk1 repression, and to loss of Rtl1 expression. lncRNA expression also correlated with DNA hypomethylation and CTCF binding at the 5’-side of Meg3. Using Capture Hi-C, we found that this creates a Topologically Associating Domain (TAD) organization that brings Meg3 close to Dlk1 on the maternal chromosome. The requirement of Meg3 for gene repression and TAD structure may explain how aberrant MEG3 expression at the human DLK1-DIO3 locus associates with imprinting disorders.

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The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Project description:Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated patient-derived induced pluripotent stem cells (iPSCs) harboring distinct deletions in the affected region on chromosome 15. Studying PWS-iPSCs and human parthenogenetic iPSCs unexpectedly revealed substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we identified IPW, a long noncoding RNA in the critical region of the PWS locus, as a regulator of the DLK1-DIO3 region, as its over-expression in PWS and parthenogenetic iPSCs results in downregulation of the MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications, rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region. Gene expression analysis was performed on a total of 4 human cell lines, including 3 Prader-Willi Syndrome indcued pluripotent stem cell lines - derived from 3 affected individuals and one of their parental fibroblast cell line.

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