FLT1 and transcriptome-wide polyadenylation site (PAS) analysis in preeclampsia

• Type of Material: Article
• Authors: Ami Ashar-Patel, University of Massachusetts; Yasin Kaymaz, University of Massachusetts; Augustine Rajakumar, Emory University; Jeffrey A. Bailey, University of Massachusetts; S. Ananth Karumanchi, Harvard Medical School; Melissa J. Moore, University of Massachusetts
• Language: English
• Date: 2017-09-22
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-11639-6
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Start Page: 12139
• End Page: 12139
• Grant/Funding Information: This study was supported by funding from the Bill and Melinda Gates Foundation Grand Challenges Exploration program and the Howard Hughes Medical Institute; M.J.M was a HHMI Investigator at the time the study was conducted.
• Keywords: PREGNANCY; PLACENTAL HYPOXIA; Molecular biology; TROPHOBLAST INVASION; VEGF RECEPTOR-1; ANGIOGENIC FACTORS; DISEASE; Science & Technology - Other Topics; Transcriptomics; Science & Technology; GENE-EXPRESSION; GROWTH-FACTOR RECEPTOR-1; ENRICHMENT ANALYSIS; Multidisciplinary Sciences; UNITED-STATES
• Research Categories: Health Sciences, Obstetrics and Gynecology; Biology, Molecular

Abstract

Maternal symptoms of preeclampsia (PE) are primarily driven by excess anti-angiogenic factors originating from the placenta. Chief among these are soluble Flt1 proteins (sFlt1s) produced from alternatively polyadenylated mRNA isoforms. Here we used polyadenylation site sequencing (PAS-Seq) of RNA from normal and PE human placentae to interrogate transcriptome-wide gene expression and alternative polyadenylation signatures associated with early-onset PE (EO-PE; symptom onset < 34 weeks) and late-onset PE (LO-PE; symptom onset > 34 weeks) cohorts. While we observed no general shift in alternative polyadenylation associated with PE, the EO-PE and LO-PE cohorts do exhibit gene expression profiles distinct from both each other and from normal placentae. The only two genes upregulated across all transcriptome-wide PE analyses to date (microarray, RNA-Seq and PAS-Seq) are NRIP1 (RIP140), a transcriptional co-regulator linked to metabolic syndromes associated with obesity, and Flt1. Consistent with sFlt1 overproduction being a significant driver of clinical symptoms, placental Flt1 mRNA levels strongly correlate with maternal blood pressure. For Flt1, just three mRNA isoforms account for > 94% of all transcripts, with increased transcription of the entire locus driving Flt1 upregulation in both EO-PE and LO-PE. These three isoforms thus represent potential targets for therapeutic RNA interference (RNAi) in both early and late presentations.