MiR455 is linked to hypoxia signaling and is deregulated in preeclampsia.

S Lalevée,O Lapaire,M Bühler

doi:10.1038/cddis.2014.368

Abstract

Preeclampsia is a severe pregnancy-related disorder and a leading cause of maternal and fetal mortality worldwide. Early identification of patients with an increased risk for preeclampsia is thus one of the most important goals in obstetrics. Here we identify two related human microRNAs as potential biomarkers to detect at-risk pregnancies. We demonstrate that miR455-3P and miR455-5P are significantly downregulated in placentas from preeclampsia patients, whereas other placenta-specific microRNAs remain unaffected. microRNA target prediction and validation revealed a potential link of miR455-3P to hypoxia signaling. Together with our observation that expression levels of miR455-3P and miR455-5P are upregulated during trophoblast differentiation, our results suggest a model in which miR455-3P represses a hypoxia response that might otherwise prevent cytotrophoblasts from syncytiotrophoblast differentiation. In summary, our work reveals aberrant hypoxia signaling in preeclampsia that can be explained by deregulated expression of miR455. As miR455 has been found in circulating blood, the development of noninvasive prenatal tests enabling early diagnosis of preeclampsia may be possible.

Highlights

MicroRNAs are a large family of post-transcriptional regulators of gene expression, circa 21 nucleotides in length, that control many developmental and cellular processes in eukaryotic organisms
Confirming the trophoblastic origin of the BeWo cell line, we found that 50% of all miRNAs sequenced from either control- or FSK-treated cells were derived from the chromosome-19-miRNA-cluster (C19MC) (Supplementary Table S1)
Compiling lists of potential targets for miR455-3P and -5P, we noted at least eight genes that have been linked to hypoxia signaling (Figure 3a). This raised our interest because miR210 expression is stimulated by hypoxia-inducible factors (HIF),[40,41,42] suggesting a potential hypoxia-related relationship between the three miRNAs we found to be differentially expressed in PE samples

Summary

Introduction

MicroRNAs are a large family of post-transcriptional regulators of gene expression, circa 21 nucleotides (nt) in length, that control many developmental and cellular processes in eukaryotic organisms. As part of miRISC, mature miRNAs base pair with sequences in the 30-UTR of target mRNAs and direct their translational repression and/or mRNA deadenylation and degradation.[12] MicroRNAs have been suggested to target the coding sequence of some mRNAs as well as the 50UTR of ribosomal protein-coding mRNAs, leading to Abbreviations: miRNA, microRNA; PE, preeclampsia; nt, nucleotide; pri-miRNA, primary microRNA; pre-miRNA, precursor microRNA; miRISC, microRNA induced silencing complex; UTR, untranslated region; C14MC, chromosome 14 microRNA cluster; C19MC, chromosome 19 microRNA cluster; CT, cytotrophoblast; SCT, syncytiotrophoblast; FSK, forskolin; DMSO, dimethylsulfoxid; DAPI, 40,60-diamidino-2-phenylindole; CGB, beta chorionic gonadotropin hormone; snRNA, small nuclear RNA; RL, renilla luciferase; FL, firefly luciferase; h, hours; HIF, hypoxia inducible factor; TBP, TATA binding protein; Ctrl, control; Ct, cycle threshold; RT-PCR, reverse transcription-polymerase chain reaction. Several studies have revealed upregulation of the miRNA miR210 in placenta from PE patients.[26,27,28,29,30] most of these studies were limited by the scarcity of placental samples needed for miRNA expression, their heterogeneity, and/or the low number of miRNAs studied.[26,30] it is not clear to what extent miRNAs other than miR210 are differentially expressed in PE patients

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Results

Conclusion