Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies

Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.

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Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3

Psychological Medicine ◽

10.1017/s0033291716001598 ◽

2016 ◽

Vol 46 (14) ◽

pp. 2999-3011 ◽

Cited By ~ 21

Author(s):

A. B. Janssen ◽

L. E. Capron ◽

K. O'Donnell ◽

S. J. Tunster ◽

P. G. Ramchandani ◽

...

Keyword(s):

Gene Expression ◽

Maternal Depression ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Prenatal Depression ◽

Placental Lactogen ◽

Maternal Behaviour ◽

Imprinted Genes ◽

Neurodevelopmental Outcomes

BackgroundMaternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression.MethodA diagnosis of depression during pregnancy was recorded from Manchester cohort participants’ medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression.ResultsIn a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively).ConclusionsThis study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

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Associations between imprinted gene expression in the placenta, human fetal growth and preeclampsia

Biology Letters ◽

10.1098/rsbl.2017.0643 ◽

2017 ◽

Vol 13 (11) ◽

pp. 20170643 ◽

Cited By ~ 8

Author(s):

Julian K. Christians ◽

Katherine Leavey ◽

Brian J. Cox

Keyword(s):

Gene Expression ◽

Genomic Imprinting ◽

Fetal Growth ◽

Placental Insufficiency ◽

Imprinted Genes ◽

Nutrient Allocation ◽

Imprinted Gene ◽

Expression Levels ◽

Kinship Theory ◽

Coordinated Regulation

Genomic imprinting is essential for normal placental and fetal growth. One theory to explain the evolution of imprinting is the kinship theory (KT), which predicts that genes that are paternally expressed will promote fetal growth, whereas maternally expressed genes will suppress growth. We investigated the expression of imprinted genes using microarray measurements of expression in term placentae. Correlations between birthweight and the expression levels of imprinted genes were more significant than for non-imprinted genes, but did not tend to be positive for paternally expressed genes and negative for maternally expressed genes. Imprinted genes were more dysregulated in preeclampsia (a disorder associated with placental insufficiency) than randomly selected genes, and we observed an excess of patterns of dysregulation in preeclampsia that would be expected to reduce nutrient allocation to the fetus, given the predictions of the KT. However, we found no evidence of coordinated regulation among these imprinted genes. A few imprinted genes have previously been shown to be associated with fetal growth and preeclampsia, and our results indicate that this is true for a broader set of imprinted genes.

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Risk stratification for early-onset fetal growth restriction in women with abnormal serum biomarkers: a retrospective cohort study

Scientific Reports ◽

10.1038/s41598-020-78631-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

L. Ormesher ◽

L. Warrander ◽

Y. Liu ◽

S. Thomas ◽

L. Simcox ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Late Onset ◽

Area Under The Curve ◽

Maternal Serum ◽

Serum Biomarkers ◽

Growth Restriction ◽

Aneuploidy Screening ◽

Internal Validation

AbstractAbnormal maternal serum biomarkers (AMSB), identified through the aneuploidy screening programme, are frequent incidental findings in pregnancy. They are associated with fetal growth restriction (FGR), but previous studies have not examined whether this association is with early-onset (< 34 weeks) or late-onset (> 34 weeks) FGR; as a result there is no consensus on management. The aims of this study were to determine the prevalence and phenotype of FGR in women with AMSB and test the predictive value of placental sonographic screening to predict early-onset FGR. 1196 pregnant women with AMSB underwent a 21–24 week “placental screen” comprising fetal and placental size, and uterine artery Doppler. Multivariable regression was used to calculate a predictive model for early-onset FGR (birthweight centile < 3rd/< 10th with absent umbilical end-diastolic flow, < 34 weeks). FGR prevalence was high (10.3%), however early-onset FGR was uncommon (2.3%). Placental screening effectively identified early-onset (area under the curve (AUC) 0.93, 95% confidence interval (CI) 0.87–1.00), but not late-onset FGR (AUC 0.70, 95% CI 0.64–0.75). Internal validation demonstrated robust performance for detection/exclusion of early-onset FGR. In this cohort, utilisation of our proposed algorithm with targeted fetal growth and Doppler surveillance, compared with universal comprehensive surveillance would have avoided 1044 scans, potentiating significant cost-saving for maternity services.

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Physiopathology of late-onset fetal growth restriction

Minerva Obstetrics and Gynecology ◽

10.23736/s2724-606x.21.04771-7 ◽

2021 ◽

Vol 73 (4) ◽

Author(s):

Edward ARAUJO JÚNIOR ◽

Ana C. ZAMARIAN ◽

Ana C. CAETANO ◽

Alberto B. PEIXOTO ◽

Luciano M. NARDOZZA

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Late Onset ◽

Growth Restriction

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miR-16-5p, miR-103-3p, and miR-27b-3p as Early Peripheral Biomarkers of Fetal Growth Restriction

Frontiers in Pediatrics ◽

10.3389/fped.2021.611112 ◽

2021 ◽

Vol 9 ◽

Author(s):

Salvatore Tagliaferri ◽

Pasquale Cepparulo ◽

Antonio Vinciguerra ◽

Marta Campanile ◽

Giuseppina Esposito ◽

...

Keyword(s):

Fetal Growth ◽

Gestational Age ◽

Fetal Growth Restriction ◽

Late Onset ◽

Maternal Blood ◽

Growth Restriction ◽

Therapeutic Interventions ◽

Control Group ◽

Fetal Hypoxia ◽

Blood Samples

Current tests available to diagnose fetal hypoxia in-utero lack sensitivity thus failing to identify many fetuses at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may be used as non-invasive biomarkers for pregnancy complications. With the intent to identify putative markers of fetal growth restriction (FGR) and new therapeutic druggable targets, we examined, in maternal blood samples, the expression of a group of microRNAs, known to be regulated by hypoxia. The expression of microRNAs was evaluated in maternal plasma samples collected from (1) women carrying a preterm FGR fetus (FGR group) or (2) women with an appropriately grown fetus matched at the same gestational age (Control group). To discriminate between early- and late-onset FGR, the study population was divided into two subgroups according to the gestational age at delivery. Four microRNAs were identified as possible candidates for the diagnosis of FGR: miR-16-5p, miR-103-3p, miR-107-3p, and miR-27b-3p. All four selected miRNAs, measured by RT-PCR, resulted upregulated in FGR blood samples before the 32nd week of gestation. By contrast, miRNA103-3p and miRNA107-3p, analyzed between the 32nd and 37th week of gestation, showed lower expression in the FGR group compared to aged matched controls. Our results showed that measurement of miRNAs in maternal blood may form the basis for a future diagnostic test to determine the degree of fetal hypoxia in FGR, thus allowing the start of appropriate therapeutic interventions to alleviate the burden of this disease.

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