Deciphering the roles of retrotransposons in human placental development and disorder

Abstract

Approximately 40% of the human genome consists of retrotransposons, which are transposable elements that replicate via an RNA-mediated “copy-and-paste” mechanism. Given their potentially deleterious effects on the genome, retrotransposons are generally repressed by epigenetic mechanisms. Intriguingly, a subset of elements has been co-opted to become integral parts of our genomes, functioning as cis-regulatory elements or as coding sequences. For instance, ERV-derived SYNCYTIN proteins play a critical role in placental development. Previous studies have also found retrotransposons to serve as tissue-specific enhancers or alternative promoters in the human placenta. These studies hint at the potential regulatory functions of retrotransposons in shaping placental transcriptomes and their involvement in placental disorders, including preeclampsia, a hypertensive pregnancy complication and the leading cause of maternal mortality due to pregnancy. Despite the abundant examples of retrotransposons’ contribution to the normal function of the placenta, the role of retrotransposons in placental disorder preeclampsia remains poorly understood. Here, I generated transcriptomic and epigenomic datasets from 17 control and preeclampsia-derived placenta samples. I performed an integrative analysis to decipher the cis-regulatory roles of retrotransposons. Notably, I discovered differentially expressed retrotransposons in the placenta of preeclampsia patients, which are associated with preeclampsia pathogenesis. Furthermore, some of the dysregulated retrotransposons can potentially drive novel transcription. In particular, I identified an MLT1B element that has features of a placenta-specific promoter for the LIN28B gene, which is dysregulated in the preeclampsia placenta. Taken together, my thesis work provides insights into the roles of retrotransposons in placenta development and disorder.

Date of Award	2020
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology