Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting

Abstract

Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methylation in humans. With the exception of a few known paternally methylated germline differentially methylated regions (DMRs) associated with known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage of development. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage and uniquely persist as transiently methylated DMRs only in the placenta. Furthermore, we demonstrate that this phenomenon is exclusive to primates, since no placenta-specific maternal methylation was observed in mouse. Utilizing single cell RNA-seq datasets from human preimplantation embryos we show that following embryonic genome activation the maternally methylated transient DMRs can orchestrate imprinted expression. However despite showing widespread imprinted expression of genes in placenta, allele-specific transcriptional profiling revealed that not all placenta-specific DMRs coordinate imprinted expression and that this maternal methylation may be absent in a minority of samples, suggestive of polymorphic imprinted methylation.

Author Summary

Differences in gamete DNA methylation is subject to genome-wide reprogramming during preimplantation development to establish an embryo with an epigenetic state compatible with totipotency. DNA sequences associated with imprinted differentially methylated regions (DMRs) are largely protected from this process, retaining their parent-of-origin epigenetic marks. By comparing the methylation profiles of human oocytes, sperm, blastocysts and various somatic tissues including placenta, we observe hundreds of CpG island sequences that maintain methylation on their maternal allele in blastocysts and placenta indicative of incomplete reprogramming. In some cases this maternal methylation influence transcription of nearby genes, revealing transient imprinting in embryos after genome-activation and in placenta. Strikingly, these placenta-specific DMRs are polymorphic between placenta samples with a minority of samples being robustly unmethylated on both alleles.