A study that was published in the journal DNA & Development demonstrates how external factors could impact a fertilised egg's genes in a way that results in foetal death.
Recent studies on laboratory mice have brought researchers one step closer to understanding the reason for miscarriage and faulty placenta development. The discoveries might affect how we think about miscarriages and how the human placenta grows.
“Miscarriage and placental abnormality are quite common in humans,” says co-author Azusa Inoue, a team leader at Japan’s Riken Center for Integrative Medical Sciences.
A miscarriage occurs in 10 to 20 percent of known pregnancies, while some argue that the true rate is higher when losses that happen before pregnancy are recognised are taken into consideration.
The results of the study undertaken by Inoue and his associates may help determine which genes affect placenta size, potentially enhancing some pregnancies’ chances of success.
Non-genetic qualities are also inherited by living beings from their parents. When sperm and eggs are transferred from parent to child during pregnancy, these epigenetic markings may be passed along as well. Some genes may be turned off and others turned on as a result of epigenetic modifications brought on by the external environment or parental conduct.
Inoue and his team investigated the histones involved in the process known as genomic imprinting, which transmits epigenetic instructions to egg cells. They were aware from earlier research that blocking a group of instructions known as histone H3 lysine 27 (H3K27) trimethylation from egg cells caused miscarriages in mice, especially for male embryos. During pregnancy, it also led to larger placentas in the moms.
Therefore, the purpose of the new study was to determine whether these incorrect instructions contributed directly to bigger placentas and perinatal fatalities. Using the gene-editing technique CRISPR, they conducted tests by inhibiting each of the nine potential offenders, genes that are generally silenced but abnormally active when mouse moms miscarry.
After all of this, Xist, a gene on the X chromosome, was shown to be the most likely culprit by Inoue and his colleagues. Male embryos were lost due to faulty epigenetic instructions from eggs on the Xist gene. Additional testing identified the genes that were improperly active when the placentas were enlarged due to the absence of epigenetic imprinting. The researchers were able to treat the placental abnormalities in some of the mouse embryos by halting this activation.
“The initial trigger of this lethality is the lack of histone modification transmitted from the mother to the fetus,” says Inoue.
However, he argues, a larger placenta isn’t always a bad thing when there is a chance of miscarriage. This abnormality may help the embryo survive a miscarriage because a bigger placenta can enable more nutrients to be transferred from the mother to the foetus.
“We realized that placenta enlargement is seen to enhance the fetal development to catch up to fetal retardation,” says Inoue. He and his colleagues are currently working on a way to induce this enlargement in cases where the fetus might not be developing normally: “We’re trying to establish a system, or an experimental strategy, to induce placenta enlargement.”
The key question is whether some human miscarriages involve comparable mechanisms. Dr. Jan Brosens, an obstetrician and gynaecologist at the University of Warwick in England who does research miscarriages but was not part in the most recent study, is uncertain about extrapolating results from mice to people.
“Embryo development and implantation are very different in humans versus mice,” he explains.
Rajiv McCoy, a biologist at Johns Hopkins University in Maryland who was also not involved in the study, adds that there is conflicting evidence about whether the mechanism of maternally-inherited modifications to histone proteins can influence gene expression during human development at all.
“[But] while the specific mechanisms may differ, it is interesting to consider whether some cases of pregnancy loss in humans could occur due to dysregulation of these imprinting systems, especially with regard to the placenta,” he says.
Inoue says that while it’s unclear whether faulty epigenetic instructions on histone proteins cause miscarriages in humans, placenta enlargement is regardless quite common.
“The Xist gene that we have identified to be responsible for the developmental lethality is present in humans,” he says. “But the epigenetic instruction does not occur on this gene in humans.”
Nevertheless, he claims that the instrument being developed by the researchers to regulate the size of placentas in mice may one day be applied to people, but only after extensive additional study.