A cause of miscarriage and developmental abnormalities has been identified, and even cured, in a new mouse study. Published in the journal Genes and Development, the paper has discovered that the expression of a gene on the X-chromosome, which should otherwise be suppressed, may be responsible for prenatal death, at least in mice.
“This study identified genes critical for fetal development whose expression is controlled by [modifications to a protein associated with DNA] transmitted from eggs to the next generation,” lead author Azusa Inoue said in a statement.
“The findings have implications for understanding infertility and developing treatments.”
The gene identified in the study, Xist, is present on the X-chromosome – one of the two sex chromosomes in humans. When an egg is fertilized, it has two of each chromosome and therefore two copies of each gene (unless it has XY sex chromosomes, in which case one copy might be missing from the stubby Y chromosome).
However, some genes can be turned on or off, so that only one copy – maternal or paternal – is expressed. This is called genomic imprinting. If the paternal gene is imprinted, it is silenced and only the maternal gene is expressed and vice versa.
Only a small percentage of genes undergo imprinting, but those that do control it by epigenetic changes to DNA. When these changes are inherited from parents, they are known as transgenerational epigenetic changes and contribute to what is known as non-canonical genomic imprinting. In mouse embryos, epigenetic markers on a certain maternal histone (a protein associated with DNA) are inherited and suppress the expression of a number of maternal genes, including Xist.
Previous studies have found that preventing these particular transgenerational epigenetic changes leads to the death of mouse embryos, particularly in males, plus an enlarged placenta in the mothers. The team behind the new study was looking to determine whether failed imprinting was behind these outcomes.
As predominantly male offspring die, the team turned their attention to genes on the sex chromosomes. Eight genes are non-canonically imprinted in mouse embryos, and only one of them is on the X-chromosome – Xist.
They began by knocking out a gene required for transgenerational epigenetic changes in eggs so that they could not be inherited by the offspring and imprinting would be prevented. When they added a knockout of the Xist gene, effectively restoring Xist imprinting, prenatal death was massively reduced and the male-skewed bias was eliminated. The authors, therefore, conclude that failed Xist imprinting is a cause of miscarriage in mice.
However, even when Xist imprinting was restored, the mothers’ placentas were still enlarged. After knocking out the other seven genes that failed to imprint, the authors were able to identify three that might be involved in aberrant placental enlargement.
“Taken together, our study provides evidence that Xist imprinting sustains embryonic development and that [non-sex-chromosome] noncanonical imprinting restrains placental overgrowth,” they write.
Although they also caveat that “it is equally possible that these defects are caused by the other effects accompanied by genome-wide loss of [transgenerational epigenetic changes].”
The researchers now hope to study exactly how transgenerational epigenetic changes are established in egg cells, and what might influence this, with a view to better understanding, and potentially treating, infertility.
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