Abstract
BackgroundGenomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages, and uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored.ResultsWe identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression, and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation-dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associated with non-canonical imprints is not maintained beyond pre-implantation development at these elements and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in the epiblast.ConclusionsThis study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development and identifies an integral role for ERVK LTR repetitive elements.
Highlights
Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes
Study design To evaluate the allelic regulation of gene expression in the embryo, we assessed the epigenetic modifications in C57BL6/Babr and CAST/EiJ reciprocal hybrid embryonic day (E) 6.5 epiblast and extra-embryonic ectoderm (ExE)
In contrast to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs) genome-wide, we found that extra-embryonic ERVK LTR promoters had relatively high CpG content (Fig. 4a) and were more likely to be in close proximity and on the same strand as an annotated transcription start site (TSS) (Fig. 4b)
Summary
Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. The regulation of imprinted mono-allelic expression was found to be due to the asymmetric deposition of an epigenetic mark, DNA methylation, in gametes [6, 7]. Imprinting classically depends on locusspecific differences in DNA methylation established in the gametes [8, 9], with the vast majority of germ line differentially methylated regions (gDMRs) being established on maternal alleles during oogenesis [10]. Despite the widespread epigenetic reprogramming, which includes the erasure of DNA methylation, reallocation of histone modification patterns, and dynamic chromatin remodeling [11], imprinted gDMRs are protected from these reprogramming events. In the post-implantation embryo, as there is re-acquisition of genomic DNA methylation, gDMRs maintain their inherited mono-allelic status through the protection of the unmethylated allele [12]
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