Integrative short-read and long-read RNA sequencing reveals the regulation of preeclampsia by alternative 3' UTRs

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder that typically arises after 20 weeks of gestation. The role of alternative polyadenylation (APA) in the development of PE remains largely unexplored. In this study, we analyzed 3' UTR APA and its regulation in PE using bioinformatics pipelines.

3' UTR APA events were identified by DaPars suite based on integrated short-read and long-read RNA sequencing data generated in our laboratory. APAFlow and DAPAFlow pipelines were developed to identify miRNA binding motifs and construct miRNA-APA regulatory networks. Functional enrichment and correlation analyses were performed to assess the roles of APA events in PE pathogenesis.

1553 PE-specific APA events are detected, with 67.5% preferentially utilizing the distal PAS, associated with the immune system. 510 differential 3' UTR APA events are identified between PE and control group, 64.3% of which favored the proximal PAS and associated with the blood-brain barrier. Results from APAFlow and DAPAFlow indicated that a large number of miRNA binding motifs are enriched in 3' UTRs during PE development. The functional analyses indicated that these specific miRNAs participate in regulation of APA events and collaborate with targeted APA genes to contribute to PE pathogenesis, particularly through mechanisms involving the blood-brain barrier and immune function.

We conducted RNA sequencing and integrative bioinformatic analyses of placental tissues from PE cases, revealing widespread 3' UTR APA events associated with disease pathogenesis. Through a miRNA-centered framework, we further delineated the regulatory mechanisms underlying APA in PE. Collectively, these findings provide novel mechanistic insights into PE and underscore APA as an additional layer of post-transcriptional regulation contributing to its etiology.