The epigenetically dispersed placenta

Two molecular opponents keep placental DNA in epigenetic suspension

April 27, 2023

Our DNA is usually inactivated through two types of markings in clearly separated sections. In the cells of the placenta however, these markings are randomly scattered throughout the entire genome. A research team has now discovered the cause for this phenomenon in mouse cells: two originally independently working enzymes compete for the same sequences and keep the placenta’s DNA in an epigenetically suspended state.

Like comments on post-it labels in a cookbook, cells add more information to their genetic material by directing enzymes to attach small hydrocarbon molecules to the DNA (DNA methylation). This provides the marked sections with a reading block. Most DNA in our cells is inactivated in such a way, but the start sequences of genes do not carry such marks. Here, an enzyme complex called “Polycomb” comes into play, which regulates the reading block in a different way. Polycomb does not chemically change the DNA itself, but rather its proteins scaffold.

Researchers from the Max Planck Institute for Molecular Genetics in Berlin and Yale School of Medicine in New Haven have found that DNA-methylating enzymes and Polycomb compete for the same genetic sections in placental cells. As a result, both types of markings are apparently randomly scattered throughout the entire genome. DNA sections modified by the two enzymes have not been shown to overlap until now. The researchers suspect that the mechanism could be part of a previously unknown type of genetic regulation.

The special role of the placenta

“Methylation stabilizes the genome and only a few sections, such as promoter regions that occur at the beginning of each gene, are spared,” explains Alexander Meissner, Director and Department Head at the Max Planck Institute for Molecular Genetics. For unknown reasons, the genome of the placenta is less methylated than the DNA of normal body cells, as Meissner's research group discovered in 2017. “Similar observations have only been made in various types of cancer. This is why we suspect that this could explain the biological parallels between tumors and the placenta.”

The placenta has features that are useful to cancer. For example, it is able to bypass the immune defense of the surrounding tissue. This is necessary because otherwise the embryo would be recognized as foreign tissue by the uterus and rejected. Furthermore, the organ grows vigorously and sprouts numerous blood vessels for nutrient supply. As a filter for toxins, it is also tolerant of harmful genetic mutations – after all, it is only needed for a relatively short time until the body separates from it shortly after birth.

Cells from mice instead of a complex organ

The human placental genome cannot be studied during development for practical and ethical reasons. And even in mice, this would be extremely difficult: “The placenta as part of the embryo fuses to the maternal tissue after implantation, and the blood vessels permeate each other, making it difficult to separate the cells for analysis,” says Raha Weigert, who is a researcher in Meissner's lab.

Therefore, the team decided to study cell cultures of cells from mice, specifically the trophoblast stem cells, which would later develop into the placenta. These cells are located on the outer surface of the embryo in the early embryonic stages.

Competition for the same molecules

The research team first analyzed long, contiguous sections of placental DNA in detail, which confirmed that the scattered methyl marks actually occur on the same molecule. Other chemical properties and the three-dimensional structure of the DNA have been inconspicuous and did not differ significantly from findings in embryonic cells.

The scaffold proteins of the genetic material, called histones, however, exhibited drastic differences to their usual state. These proteins are chemically modified by polycomb enzymes and act as an additional reading block that is used sparingly by the cell. “We observed a genome-wide increase in inhibitory histone modifications in the placenta,” says Sara Hetzel, another researcher on Meissner's team. “This is very unusual and has been a big surprise to us.” Indeed, the team was able to demonstrate that both enzymes – methyltransferases and polycomb – gather around the same DNA molecules.

An enzymatic balance

To examine how much placental cells depend on the methylation of their DNA, the researchers treated their cell culture with drugs that specifically inhibit methylating enzymes. Over time, methylation decreased – and increased again when the team stopped the treatment. “This is evidence that, unlike in ordinary body cells, methylating enzymes are constantly active in the placenta – which is unusual in our classical understanding of epigenetics,” says Weigert. When the Polycomb enzyme was inhibited, methylation increased even further. “It seems there is a kind of balance between the two enzymes,” Weigert says. “Once one is removed, the other takes over.”

The purpose of this enzymatic balance is still unknown. The researchers speculate that it could be a previously unknown type of genome regulation. “We do think that this complicated mechanism has a use in the cell, but we don't know what it is yet,” Meissner says. The group's future research projects will focus on the question of what can be learned about the placenta’s gene regulation, and about tumor diseases and their therapy.

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