Pervasive polymorphic imprinted methylation in the human placenta

Abstract

The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental-specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation.

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

“…We identified hypomethylated samples for 12 of the regions (Fig 5B), with the most affected loci being LIN28B and AGBL3 . For samples with informative polymorphisms this lack of methylation is associated with biallelic expression (Fig 5C), an observation consistent with some placenta-specific maternal gDMRs being a stochastic polymorphic trait [17]. …”

“…With the exception of a few paternally methylated gDMRs associated within known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage, persisting as maternally methylated DMRs in the placenta only, expanding the number of placenta-specific DMRs reported using high-density array based screens [10, 15–17]. Furthermore, we demonstrate that this phenomenon is exclusive to humans and non-human primates since no placenta-specific maternal methylation was observed in other mammalian species.…”

“…It has previously been reported that a significant proportion of transcripts are monoallelically expressed in cleavage embryo [17] indicating that maternally methylated placenta-specific gDMRs may regulate allelic expression at this earlier developmental time point. To ascertain if the placenta-specific gDMRs orchestrate imprinted expression, we determined allelic expression in publically available single cell embryo RNA-seq datasets for which paternal genotypes were available [18].…”

Tracing human stem cell lineage during development using DNA methylation

“…We used five independent datasets to evaluate the classification area under the ROC (AUROC) curve of the FCO signature and the stability of the FCO estimations (Supplemental Methods S1): UCB GSE80310 (Knight et al 2016), GSE74738 (Hanna et al 2016), GSE54399 (Montoya-Williams et al 2017, GSE79056 (Knight et Cold Spring Harbor Laboratory Press on April 27, 2019 -Published by genome.cshlp.org Downloaded from 20 al. 2016), GSE62924 (Rojas et al 2015).…”

“…2016), GSE62924 (Rojas et al 2015). Adult peripheral blood GSE74738 (Hanna et al 2016), GSE54399 (Montoya-Williams et al 2017. To simulate synthetic mixtures we used two additional DNA methylation data sets: GSE66459 a fetal UCB (n = 22) data set (Fernando et al 2015) and GSE43976 restricting to those samples of adult peripheral blood (n = 52) data set (Marabita et al 2013) (see Supplemental Methods S2).…”