Placental imprinting: Emerging mechanisms and functions

To reiterate what these GEITP pages continue to emphasize — any trait (phenotype) reflects the contribution of gene differences in DNA sequence, epigenetic factors, environmental effects, endogenous influences, and each individual’s microbiome. Epigenetic factors include DNA-methylation, RNA-interference, histone modulation, and chromatin remodeling. The process of “imprinting” (i.e. modification of a gene’s expression, via epigenetic mechanisms — which will affect that gene’s expression in offspring; this can be behavioral, as well as a biochemical change) in the placenta is the topic of this fantastic, thorough well-written review [see attached]. Although the review focuses on DNA methylation, other forms of epigenetic factors (listed above) must be remembered as also (likely) contributors to imprinting.

The placenta is essential for healthy pregnancy, because it supports growth of the baby, helps the mother’s body adapt, and provides a connection between mother and the developing baby. Studying gene regulation and the early steps in placental development is challenging in human pregnancy; thus, mouse models have been key in building our understanding of these processes. In particular, these studies have identified a subset of genes that are essential for placentation (i.e. formation or arrangement of a placenta in a female animal’s uterus), which are called “imprinted genes”. Imprinted genes are those that are expressed from only one copy — depending on whether they are inherited from the mother or the father. It has now become apparent that regulation of imprinted genes in placenta is often unique from that in other tissues, and there are species-specific mechanisms, allowing evolution of new imprinted genes specifically in the placenta.

Cells that make up the placenta perform many diverse functions during pregnancy — including invasion into the maternal uterus, remodeling maternal vasculature, mediating nutrient and waste exchange between mother and fetus, producing pregnancy-supporting hormones, and modulating the maternal immune system to tolerate and support pregnancy. Although the placenta primarily comprises cell types arising from the conceptus, maternal immune and endometrial cells also contribute to its development and differentiation. Signals from the placenta modulate fetal growth and development, as well as maternal physiology. Through these selective pressures, genomic imprinting is thought to have evolved in placental mammals — with parental alleles in the fetal genome competing to influence maternal resource allocation…!!

Imprinted genes are those that are expressed mono-allelically (i.e. one copy only of the gene) — based on parent of origin — and >100 imprinted genes have been identified to date in mice and humans; many have been shown to be essential for fetal growth, placentation, and/or neurological function. Furthermore, tissues that show imprinted expression of the highest number of genes are placenta and brain. Given the developmental importance and evolutionary link between genomic imprinting and placenta, a growing body of work has centered on investigating regulatory mechanisms and function of imprinted genes in placenta. In particular, genetic tools — plus the ability to access to early embryonic stages in mouse models and recent advances in low-input sequence methodologies — have led to several exciting new discoveries. The author [see attached fantastic review] discusses recent work that has revealed unique mechanisms of imprinting in mouse placenta, the role these genes play in pregnancy, and aspects that we still do not understand — including how many analogous mechanisms of these genes exist in human placenta. Far below, we have tantalized the Reader by pasting Figure 1 of this review, which shows chromosomal locations of imprinted genes in mouse. 😊 😉

As emphasized, the role of placental-specific imprinting in human development and placentation is unclear and remains challenging to study — because of the inaccessibility of early embryonic development and the species-specific nature of placental imprinting. A recent study identified an association between aberrant imprinting at a number of placental-specific imprinted loci and intrauterine growth restriction — suggesting these genes may regulate fetal growth; however, determining whether these changes are the cause, or consequence, of poor growth will require further study. New technologies in culturing human trophoblast stem cells and trophoblast organoids offer new avenues into the study of placental-specific imprinting in trophoblast differentiation and function. Furthermore, recent advances in epi-CRISPR will specifically allow modulation of epigenetic states and transcriptional levels at imprinted loci in trophoblast cells in culture, to study the cellular phenotypic consequences of gene dosage.

Widespread placental-specific imprinted DNA methylation has been observed in humans, with >100 maternal genomic differentiated methylated regions (gDMRs) identified in placental trophoblasts, a feature NOT conserved in mouse. In addition, human placental imprinting is uniquely polymorphic between individuals — which may, in part, be attributable to differences in ZFP57 and ZFP445 (zinc-finger protein) activity in human vs mouse embryogenesis. These findings suggest

that the human placenta is exceptionally permissive to inherited DNA methylation from the oocyte; however, it is yet to be shown whether any imprinted loci in the human genome is/are regulated noncanonically (i.e. pathways that are presently unknown or that deviate from any canonical paradigm).

Recent studies in human preimplantation embryos suggest that H3K27me3 is reprogrammed much more rapidly than in mouse; yet, early allelic data suggest that at least a few loci may maintain a maternal bias in H3K27me3 to the morula stage (solid ball of cells from which the blastula is formed). Nevertheless, demonstrating whether noncanonical imprinting exists in the human — presents further challenges for future study because heterozygous single-nucleotide variants (SNVs) having important parental allelic information are far more rare than in mouse hybrids; this drastically limits the number of loci that can be evaluated in any one sample. Future work will reveal the full extent of imprinting in human placenta and help elucidate whether placental-specific imprinting has a role in regulating fetal growth and maternal adaptations to pregnancy, which will be essential for our understanding of pregnancy-related pathologies.

For the young investigator just starting out in his/her career, there is enough information in this fantastic review [se attached] to last a lifetime of grant proposals. 😊 😊 [And see Figure 1 below]


PLoS Genet Apr 2020; 16: e1008709

Fig 1. Extraembryonic-specific imprinted genes in the mouse genome. Genes reported to show imprinted gene expression almost exclusively in placenta and/or

visceral endoderm [5,33,35–40]. Red genes are maternally expressed, whereas blue genes are paternally expressed. Genes that are noncanonically imprinted are

underlined. Asterisks mark genes that are imprinted by an alternative mechanism in somatic tissues.

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.