Dataset Information

Multiomics reveals placental defect underlying preeclampsia

ABSTRACT: Preeclampsia is a serious pregnancy-induced disorder unique to humans affecting 4.6% of pregnancies worldwide. Advances in the detection, prevention and treatment of preeclampsia have been poor due to our inadequate understanding of its pathogenesis. Here, we perform a multiomics study on early pregnancy placental biopsies (chorionic villus samples) from pregnancies that developed preterm and term preeclampsia compared to normotensive controls. Using an integrative statistical approach we discovered preterm preeclampsia was highly associated with lipoprotein metabolism whereas term preeclampsia was associated with inflammatory pathways and notch signaling. Melanophilin was identified as significantly reduced in early pregnancy placenta from term preeclampsia. Loss of melanophilin was required for syncytialization but excess loss disrupts syncytiotrophoblast function driving the production of antiangiogenic factors known to drive preeclampsia. Our study challenges the dogma that term preeclampsia is not associated with early placental pregnancy dysfunction and provides critical insight into the early pregnancy dysfunction underlying preeclampsia, opening up new avenues for predictive biomarker and preventative treatment discovery.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Placenta, Trophoblast Cell

DISEASE(S): Pre-eclampsia

SUBMITTER: Yimiao Yu

LAB HEAD: Eva Dimitriadis

PROVIDER: PXD059993 | Pride | 2026-06-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	191107_Ellen_CVS_112886.raw	Raw
	191107_Ellen_CVS_C1934.raw	Raw
	191107_Ellen_CVS_C1966.raw	Raw
	191107_Ellen_CVS_C3729.raw	Raw
	191107_Ellen_CVS_C4144.raw	Raw

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Publications

Multi-Omics Reveals Early Pregnancy Placental Dysfunction Associated With Preterm and Term Preeclampsia.

Menkhorst Ellen E Yang Guannan G Yu Yimiao Y Santos Leilani L LL Zhou Wei W Syngelaki Argyro A Varshney Swati S Williamson Nicholas A NA Koga Kaori K Rolnik Daniel Lorber DL da Silva Costa Fabricio F Nicolaides Kypros K Lê Cao Kim-Anh KA Dimitriadis Evdokia E

MedComm 20260526 6

Preeclampsia, a severe pregnancy-induced disorder unique to humans, affects ∼2%-8% of pregnancies globally. Strong evidence supports placental dysfunction as central to preeclampsia; however, there is inadequate understanding of the precise pathogenesis of preeclampsia. In this study, we present a comprehensive multi-omics analysis of early pregnancy placental biopsies (chorionic villus samples) from pregnancies that later developed preterm/term preeclampsia, compared to normotensive controls. U ...[more]

PMID: 42253923

Similar Datasets

Project description:Aberrant embryo implantation and suboptimal placentation can lead to (severe) complications such as preeclampsia and fetal growth restriction later in pregnancy. Current identification of high-risk pregnancies relies on a combination of risk factors, biomarkers, and ultrasound examinations, a relatively inaccurate approach. Previously, aberrant DNA methylation due to placental hypoxia has been identified as a potential marker of placental insufficiency and, hence, potential (future) pregnancy complications. The goal of the Early Prediction of prEgnancy Complications Testing, or the ExPECT study, is to validate a genome-wide, cell-free DNA (cfDNA) methylation strategy to diagnose preeclampsia accurately. More importantly, the predictive potential of this strategy is also explored to reliably identify high-risk pregnancies early in gestation. Furthermore, a longitudinal study was conducted, including sequential blood samples from pregnant individuals experiencing both uneventful and complicated gestations, to assess the methylation dynamics of cfDNA throughout these pregnancies. This study offers valuable insights into methylation changes at specific genomic regions throughout pregnancy, revealing critical differences between normal and complicated pregnancies. The power of non-invasive cfDNA methylation profiling was successfully proven, suggesting the potential to integrate this non-invasive approach into routine prenatal care. A significant strength of this study is its enzymatic digest, which enriches CpG-rich regions across the genome without the need for proprietary reagents or prior selection of regions of interest. This makes it useful for the cost-effective discovery of novel markers. Investigation of methylation patterns throughout pregnancy showed different methylation trends between unaffected and affected pregnancies. We detected differentially methylated regions (DMRs) in pregnancies complicated with preeclampsia as early as 12 weeks of gestation, with distinct differences in the methylation profile between early and late pregnancy. Two classification models were developed to diagnose and predict preeclampsia, demonstrating promising results on a small set of validation samples.

Project description:Background Preeclampsia is a hypertensive disorder of pregnancy with significant maternal and fetal health implications. While the molecular mechanisms underlying early-onset preeclampsia have been studied extensively, less is known about late-onset preeclampsia, particularly with regard to fetal sex-specific effects. Understanding transcriptional changes in the placenta may provide insight into persistent mechanisms or downstream consequences of the disease, thereby contributing to our understanding of its pathophysiology. While the initiating events of late-onset preeclampsia occur earlier in gestation, analysis of term placental tissue can reveal cumulative effects of disease processes and identify biological pathways that remain altered at delivery. Methods We conducted a cross-sectional observational analysis of placental gene expression using RNA sequencing in a subset of 58 term placentas (21 male-bearing and 37 female-bearing pregnancies) drawn from two large prospective birth cohorts. Pregnancies were classified based on clinical diagnosis of late-onset preeclampsia (diagnosed ≥20 weeks’ gestation according to ISSHP criteria) or uncomplicated and assessed for differential gene expression. Cell type proportions were estimated using CIBERSORTx from a placenta-specific reference single-cell dataset. Weighted gene co-expression network analysis identified modules of co-expressed genes associated with late-onset preeclampsia and fetal sex. Results Differential gene expression analysis identified 150 genes with altered expression in male-bearing placentas from pregnancies with late-onset preeclampsia compared to those from uncomplicated pregnancies. No differentially expressed genes were identified in female-bearing placentas. Cell type deconvolution revealed increased abundance of CD14+ monocytes and CD8+ activated T cells (log odds of 1.42 and 1.44 respectively) and reduced fetal GZMK natural killer cells (log odds of 0.60) in male-bearing placentas from affected pregnancies. In female-bearing placentas, late-onset preeclampsia was associated with increased fetal nucleated red blood cells and maternal plasma cells (log odds of 1.33 and 1.40 respectively). Male-specific co-expression analysis identified gene modules enriched for biological processes including RNA processing, immune regulation, and metabolism. Conclusions Placental transcription and cellular responses to late-onset preeclampsia differ by fetal sex. Evidence of altered immune cell composition and gene co-expression in male-bearing placentas suggests a sex-specific vulnerability. These findings highlight the importance of considering fetal sex in molecular investigation and clinical management of preeclampsia.

Project description:Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.