Non-Coding RNAs in Preeclampsia-Molecular Mechanisms and Diagnostic Potential

Abstract

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation.

Keywords: biomarkers; lncRNA; microRNA; preeclampsia.

Figure 1

MicroRNA biogenesis and mechanism of action. Primary miRNAs (pri-miRNAs) are transcribed from their genes and processed into double-stranded precursors (pre-miRNAs), by the microprocessor complex: RNA binding protein DiGeorge Syndrome Critical Region 8 (DGCR8) and Drosha. Pre-miRNAs are exported to the cytoplasm by an exportin 5 (XPO5)/RanGTP complex and processed by the RNase III endonuclease Dicer yielding a mature miRNA duplex. This step is followed by unwinding of mature miRNA duplex and loading into the Argonaute2 (Ago2)-containing, RNA-induced silencing complex (RISC) where the miRNAs repress mRNAs in a sequence-specific manner.

Figure 2

The biogenesis and functions of lncRNAs. Based on the transcriptional origin, lncRNAs are classified as exonic, intronic, antisense, enhancer, intergenic, promoter-associated and bidirectional. The vast majority of lncRNAs is transcribed by RNAP II. RNAP III catalyzes transcription of natural antisense transcripts from the antisense strand of exons, enhancer lncRNAs without poly-A tale and intronic lncRNAs in combination with spRNAP IV. In the nucleus, lncRNAs regulate gene expression by acting as transcriptional signals, scaffolds, decoys or enhancers. In the cytoplasm, lncRNAs can increase/decrease mRNA stability, act as miRNAs “sponges” or interact with proteins to form ribonucleoprotein complexes.