RNA Therapeutics Institute; Program in Bioinformatics and Integrative Biology; Division of Transfusion Medicine, Department of Medicine
Female Urogenital Diseases and Pregnancy Complications | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides
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.
Molecular biology, Transcriptomics
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DOI of Published Version
Sci Rep. 2017 Sep 22;7(1):12139. doi: 10.1038/s41598-017-11639-6. Link to article on publisher's site
Ashar-Patel A, Kaymaz Y, Rajakumar A, Bailey JA, Karumanchi SA, Moore MJ. (2017). FLT1 and transcriptome-wide polyadenylation site (PAS) analysis in preeclampsia. Open Access Articles. https://doi.org/10.1038/s41598-017-11639-6. Retrieved from https://escholarship.umassmed.edu/oapubs/3272
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This work is licensed under a Creative Commons Attribution 4.0 License.
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