Periodic Reporting for period 1 - InvADeRS (Investigating the Activity of transposon Derived Regulatory Sequences in the placenta)
Reporting period: 2019-05-01 to 2021-04-30
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.
The transposon sequences we identified to potentially regulate placental development were all primate-specific. This is consistent with previous studies that show that the majority of primate-specific regulatory DNA, (i.e. regulatory sequences not present in species other than primates), is transposon derived.
To irrevocably prove that transposons could regulate placental gene expression, we used a genetic cutting method to remove candidate transposons from the genome of placental cells in culture. We then measured the effect on nearby genes, identifying five cases where transposons acted as gene ‘enhancers’, increasing gene expression.
Our results have been disseminated through talks and posters at the following national and international conferences and seminars: In 2019 - The EpiGeneSys Conference, Francis Crick Institute, UK; The Centre for Trophoblast Research Conference, Cambridge, UK, the Epigenetics Gordon Research Conference, Holderness School, NH, USA, and The Physiological Society Departmental Seminar Scheme, University of Southampton. In 2020 - the Cold Spring Harbour Laboratory virtual transposable elements meeting. In 2021 - the Medical and Molecular Genetics virtual seminar series, King’s College London, UK and the FASEB Virtual Mobile DNA Conference.
In addition, we identified a number of genes that were regulated by transposons that are linked to placental invasion. Our candidate transposons were also predicted to bind signalling molecules important in invasion of maternal tissues. This is important because the extent of placental invasion is a principal factor in the health of a pregnancy. If the invasion process is aberrant, or incomplete, the baby may not be supplied with enough blood, leading to growth restriction, preeclampsia and/or preterm birth, or the embryo may fail to implant altogether, resulting in miscarriage. In this way, our findings contribute a novel set of candidate human genetic sequences that may be important for proper placental development and normal pregnancy. Further investigation of the genetics and regulation of these transposons in the population will improve future research into pregnancy complications, providing new avenues for research, screening of at-risk couples, diagnosis, and therapy.