Expression Profile of C19MC microRNAs in Placental Tissue in Pregnancy-Related Complications

Hromadníková, Ilona; Kotlabova, Katerina; Ondráčková, Markéta; Pirkova, Petra; Kestlerová, Andrea; Novotná, Veronika; Hympánová, Lucie; Krofta, Ladislav

doi:10.1089/dna.2014.2687

Cited by 107 publications

(92 citation statements)

References 104 publications

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“…We observed that most of the up-regulated miRs regulated genes relevant to hypoxia responses [35–39], vascular disease [40–44], metabolism [45–49], inflammation [50–51], or were previously reported in pre-eclamptic placentas [52–55]. In contrast, the down-regulated miRs were for the most part relevant for genes with a role in obesity or cancers [56–58], though several had also been reported in association with pregnancy disorders involving placental insufficiency [52, 55,59–61]. Given our focus on up-regulated miRs with the potential of down-regulating target genes, selected genes in the top 50 miRs which were differentially expressed (up-regulated) between groups are listed to the right of the figure, including miR-10b and -363 , which were further validated in subsequent studies.…”

Section: Resultsmentioning

confidence: 96%

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

et al. 2017

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Placental insufficiency leading to intrauterine growth restriction (IUGR) demonstrates perturbed gene expression affecting placental angiogenesis and nutrient transfer from mother to fetus. To understand the post-transcriptional mechanisms underlying such placental gene expression changes, our objective was to identify key non-coding microRNAs that express biological function. To this end, we initially undertook microarrays targeting microRNAs in a small sub-set of placentas of appropriate (AGA) versus small for gestational age (SGA) weight infants, and observed up-regulation of 97 miRs and down-regulation of 44 miRs in SGA versus AGA. In a larger cohort of samples (AGA, n = 21; SGA, n = 11; IUGR subset, n = 5), we validated by qRT-PCR differential expression of three specific microRNAs (miR-10b, -363 and -149) that target genes mediating angiogenesis and nutrient transfer. Validation yielded an increase in miR-10b and -363 expression of ~2.5-fold (p<0.02 each) in SGA versus AGA, and of ~3-fold (p<0.005) in IUGR versus AGA, with no significant change despite a trending increase in miR-149. To further establish a cause-and-effect paradigm, employing human HTR8 trophoblast cells, we assessed the effect of nutrient deprivation on miR expression and inhibition of endogenous miRs on target gene expression. In-vitro nutrient deprivation (~50%) increased the expression of miR-10b and miR-149 by 1.5-fold (p<0.02) while decreasing miR-363 (p<0.0001). Inhibition of endogenous miRs employing antisense sequences against miR-10b, -363 and -149 revealed an increase respectively in the expression of the target genes KLF-4 (transcription factor which regulates angiogenesis), SNAT1 and 2 (sodium coupled neutral amino acid transporters) and LAT2 (leucine amino acid transporter), which translated into a similar change in the corresponding proteins. Finally to establish functional significance we performed dual-luciferase reporter assays with 3’-insertion of miR-10b alone and observed a ~10% reduction in the 5’-luciferase activity versus the control. Lastly, we further validated by microarray and employing MirWalk software that the pathways and target genes identified by differentially expressed miRs in SGA/IUGR compared to AGA are consistent in a larger cohort. We have established the biological significance of various miRs that target common transcripts mediating pathways of importance, which are perturbed in the human IUGR placenta.

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Section: Resultsmentioning

confidence: 96%

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

et al. 2017

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“…In this regard, comparing 14 placentas from FGR pregnancies with 14 from normal pregnancies, it was recently found that hypoxic stress does not affect C19MC miRNA expression, except for downregulation of miR-500c-3p [14]. Similarly, Hromadnikova et al [17] detected a downregulation of 6 miRNAs (miR-517-5p, miR-518f-5p, miR-519a, miR-519d, miR-520a-5p, and miR-525) in placental tissues of 36 FGR pregnancies: compared to the previous studies, these results seem more robust since that authors investigated more types of miRNAs and used those that were previously demonstrated to be exclusively expressed or highly expressed in placental tissues. The significantly decreased expression of miR-519d, but not of miR-520a-5p and miR-525, was also confirmed by others on a larger cohort (50 healthy pregnancies compared with 45 FGR cases) [15].…”

Section: Resultsmentioning

confidence: 99%

Do miRNAs Play a Role in Fetal Growth Restriction? A Fresh Look to a Busy Corner

Chiofalo

Laganà

Vaiarelli

et al. 2017

BioMed Research International

107

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Placenta is the crucial organ for embryo and fetus development and plays a critical role in the development of fetal growth restriction (FGR). There are increasing evidences on the role of microRNAs (miRNAs) in a variety of pregnancy-related complications such as preeclampsia and FGR. More than 1880 miRNAs have been reported in humans and most of them are expressed in placenta. In this paper, we aimed to review the current evidence about the topic. According to retrieved data, controversial results about placental expression of miRNAs could be due (at least in part) to the different experimental methods used by different groups. Despite the fact that several authors have demonstrated a relatively easy and feasible detection of some miRNAs in maternal whole peripheral blood, costs of these tests should be reduced in order to increase cohorts and have stronger evidence. In this regard, we take the opportunity to solicit future studies on large cohort and adequate statistical power, in order to identify a panel of biomarkers on maternal peripheral blood for early diagnosis of FGR.

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“…The site‐specific expression profile suggests that this cluster plays a significant role in placental development . Expression profiling of C19MC miRNAs in placental tissue revealed differential expression between pregnancy‐related complications including IUGR and controls . Moreover, these miRNAs modulate the migration of extravillous trophoblasts, and therefore we cannot exclude that deregulated expression of C19MC miRNAs may also contribute to the IUGR observed in the present case.…”

Section: Discussionmentioning

confidence: 99%

Genomic duplication in the 19q13.42 imprinted region identified as a new genetic cause of intrauterine growth restriction

Pètre

Lorès

Sartelet³

et al. 2018

Clinical Genetics

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We report findings from a male fetus of 26 weeks' gestational age with severe isolated intrauterine growth restriction (IUGR). Chromosomal microarray analysis (CMA) on amniotic fluid cells revealed a 1.06-Mb duplication in 19q13.42 inherited from the healthy father. This duplication contains 34 genes including ZNF331, a gene encoding a zinc-finger protein specifically imprinted (paternally expressed) in the placenta. Study of the ZNF331 promoter by methylation-specific-multiplex ligation-dependent probe amplification showed that the duplicated allele was not methylated in the fetus unlike in the father's genome, suggesting both copies of the ZNF331 gene are expressed in the fetus. The anti-ZNF331 immunohistochemical analysis confirmed that ZNF331 was expressed at higher levels in renal and placental tissues from this fetus compared to controls. Interestingly, ZNF331 expression levels in the placenta have previously been reported to inversely correlate with fetal growth parameters. The original observation presented in this report showed that duplication of ZNF331 could be a novel genetic cause of isolated IUGR and underlines the usefulness of CMA to investigate the genetic causes of isolated severe IUGR.

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Expression Profile of C19MC microRNAs in Placental Tissue in Pregnancy-Related Complications

Cited by 107 publications

References 104 publications

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

Do miRNAs Play a Role in Fetal Growth Restriction? A Fresh Look to a Busy Corner

Genomic duplication in the 19q13.42 imprinted region identified as a new genetic cause of intrauterine growth restriction

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