Human trophoblasts are primarily distinguished from somatic cells by differences in the pattern rather than the degree of global CpG methylation

Abstract

The placenta is a fetal exchange organ connecting mother and baby that facilitates fetal growth in utero. DNA methylation is thought to impact placental development and function. Global DNA methylation studies using human placental lysates suggest that the placenta is uniquely hypomethylated compared to somatic tissue lysates, and this hypomethylation is thought to be important in conserving the unique placental gene expression patterns required for successful function. In the placental field, methylation has frequently been examined in tissue lysates, which contain mixed cell types that can confound results. To better understand how DNA methylation influences placentation, DNA from isolated first trimester trophoblast populations underwent reduced representation bisulfite sequencing and was compared to publicly available data of blastocyst-derived and somatic cell populations. First, this revealed that, unlike murine blastocysts, human trophectoderm and inner cell mass samples did not have significantly different levels of global methylation. Second, our work suggests that differences in global CpG methylation between trophoblasts and somatic cells are much smaller than previously reported. Rather, our findings suggest that different patterns of CpG methylation may be more important in epigenetically distinguishing the placenta from somatic cell populations, and these patterns of methylation may contribute to successful placental/trophoblast function.

Epigenetic changes regulating the epithelial-mesenchymal transition in human trophoblast differentiation

“…The enrichment for EMT as a biological process is consistent with our results obtained previously from the PCR arrays of EMT-associated genes (DaSilva-Arnold et al, 2015; DaSilva- Arnold et al, 2018; Natenzon et al, 2022). We therefore examined the correspondence between the RNA-seq results for the CTB/EVT differentiation process and a library of EMT genes assembled from multiple sources (Cheng et al, 2012; Gamage et al, 2018; Groger et al, 2012; Taube et al, 2010; Zhao et al, 2015). This list comprises 563 genes, derived mostly from cancer studies.…”

“…These are confirmed by a more recent publications highlighting the relative hypomethylation of CTB relative to other tissues (Nordor et al, 2017; Zhang et al, 2021), although their gestational studies also indicate increasing CTB methylation moving from second to third trimester. There are also two reports which examined the extent of methylation separately in CTB and EVT (Gamage et al, 2018; Novakovic et al, 2017). The firstshows a small but significant difference between trophoblast and somatic cells, but a minimal difference between CTB and EVT.…”

Unique features and emerging in vitro models of human placental development

“…However, compared to epiblast cells, trophoblast cells have less DNA methylation at the gene body regions of weakly expressed genes and intergenic regions. The placenta is thought to have the lowest DNA methylation levels among tissues, 66‐69 and the methylome of trophoblast cells are characterized by partial methylation domains (PMDs) 68,70,71 . These PMDs are the same in mice and humans, but their functional significance is unknown.…”