The placenta is crucial for the initiation and maintenance of pregnancy. Common complications of human pregnancy, such as preeclampsia, preterm birth, recurrent miscarriage, and growth restriction, affect ~20 % pregnancies and are each associated with problems with the placenta. The in utero environment also profoundly affects the future health of the baby, and is linked to adult conditions such as heart disease, diabetes and hypertension. Despite this, the placenta itself is a vastly understudied organ, and the causes of its success or failure are often unknown.
The development of the placenta, although heavily influenced by the environment, is ultimately controlled by its genetics and those of the mother. Understanding of the role of genetics in placental development are therefore vital to understanding complications of human pregnancy, as well as adult diseases that stem from early development. The InvADeRS research project sought to define the role of a poorly understood and as-yet mostly unexplored class of genetic sequences, known as transposons, in human placental development and disease.
Transposon sequences make up around 50 % of the human genome. They are relics of viral infections that have occurred throughout evolution, and most transposon sequences are silent and likely inert. However, a subset of transposons have recently been shown to regulate genes by increasing or decreasing gene activity, resulting in changes in cellular function and organism physiology. In one intriguing example, a transposon sequence was shown to extend the length of pregnancy through upregulation of a single gene.
The idea that transposons may regulate genes in the human placenta is an exciting one, and based on several lines of evidence. Firstly, in the placenta, transposon DNA tends to be in an active state. This is in contrast to other organs and tissues of the body, where transposons are silenced and have a restrictive DNA conformation. In this way, their ability to regulate genes seems increased specifically in the placenta, although as yet we do not know why. Secondly, the placenta forms a diverse array of structures and shapes in different mammals. Transposons are highly variable between different species, even closely related ones, and so this variety could very well have contributed to the rapid evolution and structural variation of the placenta. Finally, transposons in other mammals, such as mice, have been shown to regulate hundreds of genes in the placenta.
The overall objectives of the InvADeRS project were to evaluate the role of transposons in gene regulation in the human placenta, and measure their potential impact on complications of pregnancy. We found that several families of primate-specific transposons harbour the potential for regulating placental development. Our candidate transposon families positively impact placental gene expression overall, and are enriched in binding sites for molecules important for placental invasion. We identified key genes that are directly regulated by transposons in human placenta, including several required for placental invasion, demonstrating that transposon regulation is an important part of placental development in humans, and therefore their deregulation could contribute to complications of pregnancy.
