Differential Methylation of Imprinted Genes in Growth-Restricted Placentas

Abstract

A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (~1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions. We analyzed the differential DNA methylation of all known imprinted genes on 10 appropriate-for-gestational-age, clinically normal, placentas and 7 severe intrauterine growth-restricted placentas. Samples were pooled according to the diagnosis and analyzed by methylated DNA immunoprecipitation (MeDIP) on a tiling microarray platform. The distribution of the differentially methylated regions (DMRs) identified in growth-restricted placentas showed a slight tendency toward hypermethylation. Imprinted genes not expressed in placenta showed a unique DMR profile with the fewest hyper- and hypomethylated DMRs. Promoter and CpG island DMRs were sporadic and randomly distributed. The vast majority of DMR identified (~99%) were mapped in introns, showing no common sequence features. Also, by using the more advanced array data mining softwares, no significant patterns emerged. In contrast, differential methylation showed a highly significant correlation with gene length. Overall these data suggest that differential methylation changes in growth-restricted placentas occur throughout the genomic regions, encompassing genes actively expressed in the placenta. These findings warrant caution in interpreting the significance of genes carrying clustered DMRs because the distribution of DMRs in a gene may be attributed as a function of its length rather than as a specific biological role.

Neurodevelopmental consequences in offspring of mothers with preeclampsia during pregnancy: underlying biological mechanism via imprinting genes

“…Rapid advancements in the discovery of integrated regulation of neuropeptide homeostasis within the brain and placenta [63, 64] have led to the concept that the placenta may be like a “third brain” linking the developed (maternal) and developing (fetal) brains [64, 65]. Maternal perturbations are conveyed to the fetus via the placenta, in the expression of transporters that regulate the flux of glucose, amino acids, and vitamins required for growth and development [66].…”

“…Maternal perturbations are conveyed to the fetus via the placenta, in the expression of transporters that regulate the flux of glucose, amino acids, and vitamins required for growth and development [66]. Thus, the placenta serves as the “master regulator” in utero and plays a highly functional role in shaping fetal development [65]. …”

“…For example, peri-conceptional and prenatal exposures to both insufficient and excessive maternal nutrient intake have been found to leave lasting signals on the methylation profile of several imprinted domains, including imprinted genes INS, IGF2, GNASAS , and MEG3 [65]. …”

The human placenta methylome

“…In addition, Chu et al (15) found large regions of hypomethylation in placenta compared with maternal blood cells; however, the analysis was limited to chromosomes 13,18, and 21. Further study of DNA methylation in placenta is warranted because changes in placental methylation have been associated with infant growth rate, pre-eclampsia, and preterm delivery (17)(18)(19)(20)(21). Furthermore, the placenta is the key mediator of environmental exposures affecting developmental programming of the fetus, which can have long-lasting effects on health (22).…”

Progress in the understanding of the etiology and predictability of fetal growth restriction

“…Genomic imprinting is an epigenetically driven phenomenon that results in the preferential silencing of a copy of an autosomal gene while the other copy is expressed (Hutter et al 2010). Imprinted genes that are exclusively expressed in the placenta play a role in the distribution of maternal resources to the fetus (Lambertini et al 2011). According to the genetic conflict theory of imprinting, maternally imprinted genes that are paternally expressed, such as Igf2, Peg1/Mest and Peg3, promote fetal growth, while paternally imprinted genes that are maternally expressed, such as H19, Igf2r, Cdkn1c, Phlda2 and Grb10, act as growth suppressors (Miguel Constância et al 2002, Constancia et al 2005, Tunster et al 2011, Janssen et al 2016 (Fig.…”