Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: potential impact on gene expression and pathophysiology

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Abstract

Background

A normally developed placenta is integral to a successful pregnancy. Preeclampsia (PE) and intrauterine growth restriction (IUGR) are two common pregnancy related complications that maybe a result of abnormal placental development. Placental microRNAs (miRNAs) have been investigated as potential biomarkers for these complications, as they may play a role in placental development and pathophysiology by influencing gene expression. The purpose of this study is to utilize next-generation sequencing to determine miRNA and gene expression in human placental (chorionic villous) samples from three distinct patient groups with early-onset (EO) PE, IUGR, or PE + IUGR.

Methods

Placental tissues were collected from four patient groups (control [ N = 21], EO-PE [ N = 20], EO-IUGR [ N = 18], and EO-PE + IUGR [ N = 20]), and total RNA was used for miRNA and RNA sequencing on the Illumina Hiseq2000 platform. For stringent differential expression analysis multiple analysis programs were used to analyze both expression datasets in each patient group compared to gestational age-matched controls.

Results

Analysis revealed miRNAs and genes that are disease-specific, as well as others that were common between disease groups, which suggests common underlying placental pathologies in EO-PE and EO-IUGR. More specifically, 6 miRNAs and 22 genes were identified to be differentially expressed in all three patient groups. In addition, integrative analysis between the miRNA and gene expression datasets revealed candidate gene targets for miRNAs of interest.

Conclusions

Integration of miRNA and RNA profiling in the same three subgroups of pregnancy complications, provides an alternate level of molecular information, in addition it can be used to better understand both unique and common molecular mechanisms involved in the pathophysiology of these diseases.

Electronic supplementary material

The online version of this article (10.1186/s12920-019-0548-x) contains supplementary material, which is available to authorized users.

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Most cited references 30

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MicroRNA-directed transcriptional gene silencing in mammalian cells.

Daniel Kim, Pal Saetrom, Ola Snøve … (2008)

MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level in the cytoplasm, but recent findings suggest additional roles for miRNAs in the nucleus. To address whether miRNAs might transcriptionally silence gene expression, we searched for miRNA target sites proximal to known gene transcription start sites in the human genome. One conserved miRNA, miR-320, is encoded within the promoter region of the cell cycle gene POLR3D in the antisense orientation. We provide evidence of a cis-regulatory role for miR-320 in transcriptional silencing of POLR3D expression. miR-320 directs the association of RNA interference (RNAi) protein Argonaute-1 (AGO1), Polycomb group (PcG) component EZH2, and tri-methyl histone H3 lysine 27 (H3K27me3) with the POLR3D promoter. Our results suggest the existence of an epigenetic mechanism of miRNA-directed transcriptional gene silencing (TGS) in mammalian cells.

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Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes.

Shan-Shun Luo, Osamu Ishibashi, Gen Ishikawa … (2009)

In this study, we performed small RNA library sequencing using human placental tissues to identify placenta-specific miRNAs. We also tested the hypothesis that human chorionic villi could secrete miRNAs extracellularly via exosomes, which in turn enter into maternal circulation. By small RNA library sequencing, most placenta-specific miRNAs (e.g., MIR517A) were linked to a miRNA cluster on chromosome 19. The miRNA cluster genes were differentially expressed in placental development. Subsequent validation by real-time PCR and in situ hybridization revealed that villous trophoblasts express placenta-specific miRNAs. The analysis of small RNA libraries from the blood plasma showed that the placenta-specific miRNAs are abundant in the plasma of pregnant women. By real-time PCR, we confirmed the rapid clearance of the placenta-specific miRNAs from the plasma after delivery, indicating that such miRNAs enter into maternal circulation. By using the trophoblast cell line BeWo in culture, we demonstrated that miRNAs are indeed extracellularly released via exosomes. Taken together, our findings suggest that miRNAs are exported from the human placental syncytiotrophoblast into maternal circulation, where they could target maternal tissues. Finally, to address the biological functions of placenta-specific miRNAs, we performed a proteome analysis of BeWo cells transfected with MIR517A. Bioinformatic analysis suggests that this miRNA is possibly involved in tumor necrosis factor-mediated signaling. Our data provide important insights into miRNA biology of the human placenta.

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Pre-eclampsia: pathophysiology, diagnosis, and management

Jennifer Uzan, Marie Carbonnel, Olivier Piconne … (2011)

The incidence of pre-eclampsia ranges from 3% to 7% for nulliparas and 1% to 3% for multiparas. Pre-eclampsia is a major cause of maternal mortality and morbidity, preterm birth, perinatal death, and intrauterine growth restriction. Unfortunately, the pathophysiology of this multisystem disorder, characterized by abnormal vascular response to placentation, is still unclear. Despite great polymorphism of the disease, the criteria for pre-eclampsia have not changed over the past decade (systolic blood pressure >140 mmHg or diastolic blood pressure ≥90 mmHg and 24-hour proteinuria ≥0.3 g). Clinical features and laboratory abnormalities define and determine the severity of pre-eclampsia. Delivery is the only curative treatment for pre-eclampsia. Multidisciplinary management, involving an obstetrician, anesthetist, and pediatrician, is carried out with consideration of the maternal risks due to continued pregnancy and the fetal risks associated with induced preterm delivery. Screening women at high risk and preventing recurrences are key issues in the management of pre-eclampsia.

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Author and article information

Contributors

Zain Awamleh: 5196858500 , zawamleh@uwo.ca

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8794

Publication date (Electronic): 27 June 2019

Publication date PMC-release: 27 June 2019

Publication date Collection: 2019

Volume: 12

Electronic Location Identifier: 91

Affiliations

[1 ]GRID grid.413953.9, Children’s Health Research Institute, ; 800 Commissioners Road East, London, ON N6C 2V5 Canada

[2 ]ISNI 0000 0004 1936 8884, GRID grid.39381.30, Department of Biochemistry, , The University of Western Ontario, ; London, ON N6A 3K7 Canada

Article

Publisher ID: 548

DOI: 10.1186/s12920-019-0548-x

PMC ID: 6598374

PubMed ID: 31248403

SO-VID: 691930f4-6d00-40ee-87c1-0f1287262524

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 19 November 2018

Date accepted : 5 June 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100008093, Schulich School of Medicine and Dentistry;

Award ID: NA

Award Recipient : Zain Awamleh

Funded by: FundRef http://dx.doi.org/10.13039/501100000031, Institute of Human Development, Child and Youth Health;

Award ID: 15579

Award ID: 15262

Award Recipient : Victor K. M. Han

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: intrauterine growth restriction,microrna,next-generation sequencing,placenta,preeclampsia

Data availability:

ScienceOpen disciplines: Genetics

Keywords: intrauterine growth restriction, microrna, next-generation sequencing, placenta, preeclampsia

Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: potential impact on gene expression and pathophysiology

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Animal models of intrauterine growth restriction (IUGR)

Most cited references 30

MicroRNA-directed transcriptional gene silencing in mammalian cells.

Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes.

Pre-eclampsia: pathophysiology, diagnosis, and management

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