About this item:

220 Views | 472 Downloads

Author Notes:

Correspondence and requests for materials should be addressed to M.J.M. (email: melissa.moore@umassmed.edu)

M.J.M. conceived of the project, A.R. collected the samples and prepared total RNA, and A.A.P. made PAS-Seq libraries and performed data analysis. Y.K. wrote custom pipelines for analyzing PAS-Seq data.

M.J.M. and A.A.P. wrote the main manuscript text and A.A.P. prepared figures.

J.A.B. and S.A.K. provided material support, expert advice and participated in manuscript editing.

All authors reviewed the manuscript.

We would like to acknowledge Hakan Ozadam, Alan Derr, and Manuel Garber for technical help with bioinformatics analyses and Nathan Lawson for insightful discussions.

S.A.K. is a co-inventor on multiple patents for preeclampsia diagnostics and therapies that are held by Beth Israel Deaconess Medical Center and reports serving as a consultant to Thermofisher Scientific and has financial interest in Aggamin LLC.

The remaining authors report no conflicts.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • GROWTH-FACTOR RECEPTOR-1
  • GENE-EXPRESSION
  • ANGIOGENIC FACTORS
  • TROPHOBLAST INVASION
  • ENRICHMENT ANALYSIS
  • PLACENTAL HYPOXIA
  • VEGF RECEPTOR-1
  • UNITED-STATES
  • DISEASE
  • PREGNANCY
  • Molecular biology
  • Transcriptomics

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

Tools:

Journal Title:

Scientific Reports

Volume:

Volume 7

Publisher:

, Pages 12139-12139

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2017 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote