DNA methyltransferases and TETs in the regulation of differentiation and invasiveness of extra-villous trophoblasts

Abstract

Specialized cell types of trophoblast cells form the placenta in which each cell type has particular properties of proliferation and invasion. The placenta sustains the growth of the fetus throughout pregnancy and any aberrant trophoblast differentiation or invasion potentially affects the future health of the child and adult. Recently, the field of epigenetics has been applied to understand differentiation of trophoblast lineages and embryonic stem cells (ESC), from fertilization of the oocyte onward. Each trophoblast cell-type has a distinctive epigenetic profile and we will concentrate on the epigenetic mechanism of DNA methyltransferases and TETs that regulate DNA methylation. Environmental factors affecting the mother potentially regulate the DNA methyltransferases in trophoblasts, and so do steroid hormones, cell cycle regulators, such as p53, and cytokines, especially interlukin-1β. There are interesting questions of why trophoblast genomes are globally hypomethylated yet specific genes can be suppressed by hypermethylation (in general, tumor suppressor genes, such as E-cadherin) and how invasive cell-types are liable to have condensed chromatin, as in metastatic cancer cells. Future work will attempt to understand the interactive nature of all epigenetic mechanisms together and their effect on the complex biological system of trophoblast differentiation and invasion in normal as well as pathological conditions.

Impact of seasonality, storage of semen, and sperm head‐shape on whole tissue methylation and expression of methylation responsive candidate genes in swine placenta and fetal livers from summer and winter breedings

“…Ficz et al () proposed that genome hydroxymethylation and methylation were linked to pluripotency and lineage commitment during differentiation of embryonic stem cells, however, our data suggest that environment can plausibly influence this balance. Furthermore, placental formation involving differentiation and subsequent endometrial invasion of trophoblast cells requires a spatio‐temporal flux of DNMTs and TET proteins, both families are methylation‐responsive, to coordinate the transcriptional activation of key genes (e.g., Chorionic Gonadotropin, Nanog, Snail, E‐cadherin, Estrogen Receptor‐β ; Logan et al, ). It is also interesting to note that day‐length has been associated with DNA methylation of promoter regions for target genes of the hypothalamic‐gonadal‐axis in seasonal breeding mammals (Stevenson & Prendergast, ).…”

“…While the placental ratio of 5mC to 5hmC suggested that pregnancies generated during the winter period had greater transcriptional activity potential. The ratio for each tissue appears families are methylation-responsive, to coordinate the transcriptional activation of key genes (e.g., Chorionic Gonadotropin, Nanog, Snail, Ecadherin, Estrogen Receptor-β; Logan et al, 2013). It is also interesting to note that day-length has been associated with DNA methylation of promoter regions for target genes of the hypothalamic-gonadal-axis in seasonal breeding mammals (Stevenson & Prendergast, 2013).…”

“…Soon after fertilization, the male genome is vastly demethylated while the female genome is partially demethylated continuing through the cleavage stage (Hackett and Surani, 2013;Svoboda, 2017). After implantation, an another wave of de novo methylation occurs in the developing embryo/fetus, which then decreases during differentiation (Logan, Mitchell, & Lobie, 2013). Methylation activity within developing embryonic and extraembryonic tissues influences genes that have a direct or indirect impact on differentiation and/or trophoblast cell invasion (Logan et al, 2013).…”

“…After implantation, an another wave of de novo methylation occurs in the developing embryo/fetus, which then decreases during differentiation (Logan, Mitchell, & Lobie, 2013). Methylation activity within developing embryonic and extraembryonic tissues influences genes that have a direct or indirect impact on differentiation and/or trophoblast cell invasion (Logan et al, 2013). Interestingly, imprinted differentially methylated regions are extremely similar across somatic tissues, with the exception of the placenta (Court et al, 2014).…”

“…Several candidate genes that are regulated by DNA methylation or that have germline differentially methylated regions, have been identified and characterized within placental and/or fetal tissues (Logan et al, 2013;Court et al, 2014;Hanna et al, 2016). Most characterization of these genes has occurred in rodent and human models.…”