MicroRNA-mRNA Networks in Pregnancy Complications: A Comprehensive Downstream Analysis of Potential Biomarkers

Abstract

Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans. The majority of pregnancy complications initiate due to abnormal placental development and function. During the last decade, the role of microRNAs (miRNAs) in regulating placental and fetal development has become evident. Dysregulation of miRNAs in the placenta not only affects placental development and function, but these miRNAs can also be exported to both maternal and fetal compartments and affect maternal physiology and fetal growth and development. Due to their differential expression in the placenta and maternal circulation during pregnancy complications, miRNAs can be used as diagnostic biomarkers. However, the differential expression of a miRNA in the placenta may not always be reflected in maternal circulation, which makes it difficult to find a reliable biomarker for placental dysfunction. In this review, we provide an overview of differentially expressed miRNAs in the placenta and/or maternal circulation during preeclampsia (PE) and intrauterine growth restriction (IUGR), which can potentially serve as biomarkers for prediction or diagnosis of pregnancy complications. Using different bioinformatics tools, we also identified potential target genes of miRNAs associated with PE and IUGR, and the role of miRNA-mRNA networks in the regulation of important signaling pathways and biological processes.

Keywords: biomarkers; intrauterine growth restriction; miR-210; miRNAs; preeclampsia.

Figure 1

(A) Number of observations linking upregulated and downregulated miRNAs to PE. A total of 15 different studies linked upregulation of miR-210 with the pathogenesis of PE, eight times in circulation and seven times in the placenta. (B) Number of observations linking upregulated and downregulated miRNAs to IUGR. Three different studies linked upregulation of miR-424 with the pathogenesis of IUGR, one time in circulation and two times in the placenta. Bars rising above zero x-axis reference line indicate upregulation, and bars hanging below zero x-axis reference line indicate downregulation. A complete list of miRNAs and the number of studies linking them to each disease is in Table S5. Let-7*: let-7a, let-7b, let-7c, let-7e, let-7f, let-7g or let-7i.

Figure 2

Comparison of total miRNAs linked to PE and IUGR (A), upregulated and downregulated miRNAs in PE and IUGR (B), different groups of miRNAs linked to PE (C), and different groups of miRNAs linked to IUGR (D). PE, preeclampsia; IUGR, intrauterine growth restriction; C, circulation; P, placenta.

Figure 3

Pathways (A) and gene ontologies for biological processes (B), derived from Protein Analysis Through Evolutionary Relationships (PANTHER) classification system (v.16.0), and the number of genes associated with them. The target genes of 17 PE-linked miRNAs from genes List 1 were used in this analysis. A complete list of pathways and biological processes and genes linked with labeled pathways or biological processes is provided in Table S6.

Figure 4

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of target genes of PE-linked miRNAs from genes in List 2, derived using ClueGO (version 2.5.1) and Cluepedia (version 1.5.7) plugin in Cytoscape (version 3.8.2) environment. A complete list of KEGG pathways regulated by PE-linked miRNAs is provided in Table S7.

Figure 5

Gene ontology enrichment analysis for biological processes of target genes of PE-linked miRNAs from genes List 2, derived using ClueGO (version 2.5.1) and Cluepedia (version 1.5.7) plugin in Cytoscape (version 3.8.2) environment. A complete list of biological processes regulated by PE-linked miRNAs is provided in Table S7.

Figure 6

KEGG pathways enrichment analysis of target genes of IUGR-linked miRNAs from genes List 2, derived using ClueGO (version 2.5.1) and Cluepedia (version 1.5.7) plugin in Cytoscape (version 3.8.2) environment. A complete list of KEGG pathways regulated by IUGR-linked miRNAs is provided in Table S7.

Figure 7

Gene ontology enrichment analysis for biological processes of target genes of IUGR-linked miRNAs from genes List 2, derived using ClueGO (version 2.5.1) and Cluepedia (version 1.5.7) plugin in Cytoscape (version 3.8.2) environment. A complete list of biological processes regulated by IUGR-linked miRNAs is provided in Table S7.

Figure 8

Gene ontology enrichment analysis for biological processes of miR-210 target genes from genes List 2, derived using ClueGO (version 2.5.1) and Cluepedia (version 1.5.7) plugin in Cytoscape (version 3.8.2) environment. A complete list of biological processes regulated by miR-210 is provided in Table S7.