Abstract
Genomic imprinting at the Delta-like 1 (Dlk1)–Maternally expressed gene 3 (Meg3) locus is regulated by the Meg3 differentially methylated region (DMR), but the mechanism by which this DMR acts is unknown. The goal of this study was to analyze the Meg3 DMR during imprinting establishment and maintenance for the presence of histone modifications and trans-acting DNA binding proteins using chromatin immunoprecipitation. In embryonic stem (ES) cells, where Meg3 is biallelically expressed, the DMR showed variable DNA methylation, with biallelic methylation at one region but paternal allele-specific methylation at another. All histone modifications detected at the Meg3 DMR of ES cells were biallelic. In embryonic day 12.5 (e12.5) embryos, where Meg3 is maternally expressed, the paternal Meg3 DMR was methylated, and activating histone modifications were specific to the maternal DMR. DNA-binding proteins that represent potential regulatory factors were identified in both ES cells and embryos.
Highlights
Genomic imprinting is the differential expression of the two alleles of a gene based on their parent of origin
To determine the allele-specific methylation status of the Maternally expressed gene 3 (Meg3) differentially methylated region (DMR) in embryonic stem (ES) cells and e12.5 embryos, the DMR was first analyzed for single nucleotide polymorphisms (SNPs) between two mouse subspecies: Mus musculus domesticus and Mus musculus castaneus
Our data suggest that the epigenetic status of the Meg3 DMR in ES cells represents a window into the establishment phase of the Delta-like 1 (Dlk1)-Meg3 imprint, with key paternal silencing marks still being applied, while the epigenetic status of e12.5 embryos represents a fully mature imprint
Summary
Genomic imprinting is the differential expression of the two alleles of a gene based on their parent of origin. For a gene to be imprinted, each chromosome must be marked such that the transcriptional machinery is able to distinguish the parental alleles. Examples of such imprinting marks are DNA (CpG) methylation and covalent modifications to histone proteins. DNA methylation is applied in a parent-of-origin specific manner at CpG islands within differentially methylated regions (DMRs). Core histone proteins have N-terminal tails to which acetyl, methyl, SUMO, ubiquitin, and phosphate groups can be added to influence expression of associated genes
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