Differential Transcript Usage in the Placenta in Early Onset Preeclampsia

INTRODUCTION:Early onset preeclampsia (EOPE), a complex complication of pregnancy, is a major contributor to maternal and fetal morbidity and mortality. The only symptom consistently observed in EOPE is new maternal hypertension. Other symptoms vary among patients, posing challenges for early detection. There are currently no clinically accepted molecular markers other than FLT1, which is highly upregulated and displays a small change in its splicing ratio in EOPE placentas. However, an exhaustive search for changes in transcript use in EOPE has not been performed. METHODS:Differential transcript usage (DTU) analysis was conducted between placental samples of women with and without EOPE for four public RNA sequencing datasets. To identify changes due to placental age, DTU events were compared to preterm placentas. Selected DTUs were experimentally validated in an independent cohort. RESULTS:We identified 43 DTU events between term-birth and EOPE placentas in more than one dataset, and attributed 3 of the 43 to placental age. The genes that carry those DTUs were enriched for cell junction and cell membrane-associated pathways, which were previously suggested to be altered in preeclampsia at the gene expression level, although the alteration was mediated by other genes. DISCUSSION:Alterations in transcript usage are part of the EOPE molecular mechanism. The validated DTUs in FLT4, ADGRG6, MXI1, and LCP1 may contribute to the development of EOPE. Surprisingly, the splicing change in FLT4 takes place in the intracellular domain, whereas the preeclampsia-associated changes in its paralog FLT1 are in the extracellular domain.