In rare cases, life-threatening preeclampsia can occur during pregnancy. Now researchers have found new clues as to how this complication occurs. According to this, viral DNA fragments that are leftover in our genome control certain genes in the cells of the placenta. However, when these genes become dysregulated, placental developmental disorders and preeclampsia can occur. The findings also suggest that a specific gene could be suitable as a biomarker for the early detection of preeclampsia.
About five percent of all pregnant women suffer from what is known as preeclampsia. The mother’s metabolism is disrupted and high blood pressure and edema occur, which can be extremely dangerous or even life-threatening for both the mother and the unborn baby. Preeclampsia cannot be treated, which is why, in severe cases, premature birth and removal of the placenta are necessary. So far, little is known about the cause of this pregnancy disorder – also because it is so difficult to examine.
A team led by Rabia Anwar from the Max Delbrück Center for Molecular Medicine in Berlin has now examined in more detail what role genes play in preeclampsia. The researchers focused on DNA sections that originally came from ancient viruses. During infections, these DNA sections have been introduced into the human genome over millions of years. Most are harmless and inactive remnants, but some viral DNA building blocks have now taken on a function in the human organism. Such DNA fragments are particularly important in organs such as the placenta, which develop relatively quickly. Anwar and her colleagues therefore took samples of placental tissue from almost 300 healthy pregnant women and around 100 women with preeclampsia. Using an AI-based deep learning model, they then looked for DNA sequences in the cells that regulate gene expression.
Viral DNA fragments control genes in the placenta
The analyzes revealed that 87 of these once-viral DNA fragments now regulate genes that control the normal development and function of the placenta. Among the DNA sections were nine so-called ERV3-MLT1 enhancers, all of which come from the same retrovirus family and were dysregulated in preeclampsia samples: They strengthen or weaken the activity of a total of nine genes in the placenta cells. Four of these genes have already been suspected of being linked to preeclampsia; the five others are new discoveries. One of these genes, EPS8L1, was upregulated in all samples from preeclampsia patients. It could therefore be one of the causes of the disease. The team then tested this theory in further tests with placenta cell cultures.
It turned out that the EPS8L1 gene is only active in the trophoblasts – the cells that form the outer layer of the blastocyst in the first days of pregnancy and later become the placenta. If the gene is overactive due to the viral amplifiers, the trophoblasts are less able to implant. As a result, the placenta exhibits altered blood vessels, oxidative stress and tissue damage, which can later lead to preeclampsia. However, if the EPS8L1 gene is completely switched off, the trophoblasts die and the placenta also develops incorrectly. The biomedical scientists conclude from their experiments that the gene is required for the normal function of the placenta and must not be either too active or too little active.
Early detection of preeclampsia using a blood test?
In addition, the team found that the EPS8L1 protein is present not only in the trophoblasts and placental cells, but also in the mother’s blood. The protein could be detected in the blood as early as the 24th week of pregnancy. What was striking was that the more EPS8L1 protein there was in the blood, the higher the typical blood values for preeclampsia. This connection could possibly be used for early detection in the future: instead of using complex tissue samples, simple blood tests could be used to check whether this gene functions normally in pregnant women or is overactive. “The findings point to a potential biomarker that can be used to detect the risk of preeclampsia in the first trimester of pregnancy, long before dangerous symptoms appear,” says senior author Zsuzsanna Izsvák from the Max Delbrück Center. Whether this biomarker works reliably in all pregnant women now needs to be tested in larger clinical studies.
Source: Rabia Anwar (Max Delbrück Center for Molecular Medicine) et al.; genome biology, doi: 10.1186/s13059-025-03821-1