An epigenetic cause of miscarriages is identi

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image: Cartoon rendering of the first experiment. (Left) The normal situation in wild-type mice. (Middle) When ova lack H3K27 trimethylation, maternal Xist is active and lethal to males. (Right) Supplemental knockout (KO) of maternal Xist prevents male-biased prenatal death (miscarriage). Other knockouts of other genes that failed to imprint rescued the enlarged maternal placenta (not shown).
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Researchers led by Azusa Inoue at the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have discovered a gene responsible for prenatal death when critical transgenerational instructions are missing from egg cells. Posted on April 28 in Genes & Developmentthe study shows that in mice, failure of epigenetic deletion of an X chromosome gene called exists leads to miscarriages and developmental abnormalities.

“This study identified genes critical for fetal development whose expression is controlled by histone modifications passed down from eggs to the next generation,” Inoue explains. “The findings have implications for understanding infertility and developing treatments.”

For embryos to develop normally, eggs and sperm must receive important biological instructions before they meet. Once an egg is fertilized, some of these instructions tell the genes to be turned on or off depending on whether they come from the mother or the father. This process is called genomic imprinting and is the subject of the new study.

When changes in gene expression are passed on to the next generation, they are called transgenerational epigenetic changes because they are heritable changes even though the DNA code remains unchanged. Inoue and his team studied a specific set of transgenerational epigenetic instructions given to egg cells called histone H3 lysine 27 (H3K27) trimethylation. In previous studies, they found that preventing these instructions led to prenatal death, especially for male embryos, as well as placental enlargement in mothers. The new study asked whether these findings were directly related to impression failure.

The study began by knocking out a gene needed for H3K27 trimethylation in eggs so that transgenerational instructions could not be given. Then the team added a knockout of the exists gene to these eggs. Because male offspring tended to die, the researchers suspected the culprit was a gene on the sex chromosome. It turns out that there are nine maternal genes known to be deleted in embryos in favor of those of paternal origin. And only one, existsis on the X chromosome.

The results were almost as expected. Prenatal mortality was significantly reduced and male-biased lethality disappeared after stunning exists. It showed that he failed exists the imprint was the reason for the prenatal death. However, the placenta was still enlarged. Believing it was likely overexpression related to the other eight genes that failed to imprint, the team created eight different deletion mutants in the double-knockout embryos. They found that for three of the genes, this resulted in normal-sized placentas.

“We successfully cured developmental defects in a mouse model that otherwise suffers from prenatal lethality and placental malformation due to lack of transgenerational epigenetic instruction from mothers,” Inoue explains. The researchers plan to conduct further experiments to determine how these specific biological instructions are established during egg creation and whether environmental factors may influence the process.

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Reference:
Matoba et al. (2022) Non-canonical imprint supports embryonic development and limits placental proliferation. Genes Dev. doi: 10.1101/gad.349390.122


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