Project description:Preeclampsia (PE) is a common pregnancy disorder, and it complicates 5~7% of all pregnancies. At present, termination of pregnancy is the only curative strategy for PE. To explore a potential target for PE treatment, we collected placental tissue samples from patients with preeclampsia (PE) and normal pregnant women (N), and performed high-throughput RNA sequencing. We found that FOXP2 was significantly downregulated in placental samples of patients with PE compared with the controls.
Project description:Background: Hypertensive disorders of pregnancy (HDP) comprise a spectrum of four subtypes: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia (PE), and superimposed preeclampsia (siPE). Although often characterized as a spectrum of disease severity, there have been limited comparative studies of detailed clinical and molecular characteristics of these disorders. We hereby evaluate HDP subtypes using clinical, placental histopathological and molecular data to compare the similarities and differences between HDP subtypes. Methods: We utilize data from over 10-year-long pregnancy cohort with detailed clinical and placental pathology, as well as placental tissue RNA-sequencing. Clinical diagnosis was based on current ACOG criteria, and placental gross and histologic examination was based on the Amsterdam consensus statement. Results: Clinical data analysis showed cHTN and gHTN to be more likely to have normal placental pathology, while PE and siPE were more enriched in maternal vascular malperfusion (MVM). RNA-seq showed distinct gene expression signatures and pathway activation across our HDP subgroups. We could not identify any molecular evidence that preeclampsia (PE or siPE) was an advanced stage of hypertensive disorder (gHTN or cHTN), but rather identified distinct gene expression profiles between these entities, suggesting preeclampsia (PE or siPE) and hypertension (gHTN or cHTN) are distinct pathophysiological conditions. Finally, we found that, in the presence of MVM, siPE and PE share significant gene expression profiles and pathway activation. Conclusion: Our findings suggest that MVM specifically differentiates pregnancies that progress to PE and siPE. MVM is thought to initiate in early gestation, indicating the cascade to PE/siPE maybe differentiated from gHTN/cHTN early in pregnancy. Incorporating placental evaluation into patient care is essential, in order to probe the etiology of HDP.
Project description:Background: A small number of recent reports have suggested that altered placental DNA methylation may be associated with early onset preeclampsia. It is important that further studies be undertaken to confirm and develop these findings. We therefore undertook a systematic analysis of DNA methylation patterns in placental tissue from 24 women with preeclampsia and 24 with uncomplicated pregnancy outcome. Methods: We analyzed the DNA methylation status of approximately 27,000 CpG sites in placental tissues in a massively parallel fashion using an oligonucleotide microarray. Follow up analysis of DNA methylation at specific CpG loci was performed using the Epityper MassArray approach and high-throughput bisulfite sequencing. Results: Preeclampsia-specific DNA methylation changes were identified in placental tissue samples irrespective of gestational age of delivery. In addition, we identified a group of CpG sites within specific gene sequences that were only altered in early onset-preeclampsia (EOPET) although these DNA methylation changes did not correlate with altered mRNA transcription. We found evidence that fetal gender influences DNA methylation at autosomal loci but could find no clear association between DNA methylation and gestational age. Conclusion: Preeclampsia is associated with altered placental DNA methylation. Fetal gender should be carefully considered during the design of future studies in which placental DNA is analyzed at the level of DNA methylation. Further large-scale analyses of preeclampsia-associated DNA methylation are necessary. Bisulphite converted DNA from the 48 samples were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2
Project description:The etiology of preeclampsia, a hypertensive disorder of human pregnancy, remains unknown. We addressed fetal sex selection and the suggestive role of fetal HLA-G and related genes, regulating maternal immune responses, in preeclampsia pathogenesis. We assessed birth sex ratios, weights, and seasonality of preeclampsia among 1.79 million births in Finland. We studied haplotypes of HLA-G 3’ untranslated region (UTR), regulating HLA-G expression, in 1000 Genomes series and in a preeclampsia cohort (n=1249). We quantified placental (n=163) mRNA expression of 136 genes, studied HLA-G and IFNα protein expression by immunohistochemistry, and measured maternal and fetal circulating IFNα levels by ELISA. Population-level data showed loss of male fetuses as a characteristic of preeclampsia. As a potential contributor to immune-mediated loss, we found balancing selection at HLA-G 3’UTR modulating sex ratio, and association of HLA-G 3’UTR haplotypes with placental HLA-G expression. HLA-G and its receptors were downregulated in preeclampsia placentas, and surprisingly, interferon alpha-1 (IFNA1) was highly upregulated. IFNA1 and HLA-G distinguished preeclampsia better than placental FLT1 expression. Fetal but not maternal circulating IFNα, produced by trophoblasts, showed association with maternal hypertension and fetal growth restriction. We uncover the link between placental HLA-G expression and human birth sex ratio. We propose that preeclampsia shares, through reduced HLA-G mediated immunotolerance, the mechanism needed to fight placental viral infections and malaria in evolution. IFNα upregulation in preeclampsia placenta, together with its known actions upstream of inflammatory genes, encourages testing IFNα inhibitors and especially the pregnancy-approved antimalarial hydroxichloroquine in treatment of preeclampsia.
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:The tubal ectopic pregnancy (TEP) is a severe pregnancy complication accounted for 10-15% pregnancy-related deaths owing to the implantation and growth of embryos in fallopian tubes. Placental villi from TEP exhibit significant difference compared with that from intrauterine pregnancy (IP) in total volumes, trophoblast differentiation and intravillous vascularization. To investigate the difference in expression profiles of placental villi from IP and TEP, placental villi were collected from each phenotype, separated from maternal tissues and analyzed by high-throughput sequencing.
Project description:The placenta mediates adverse pregnancy outcomes, including preeclampsia, characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue at term. We deconvoluted eight published microarray case-control studies of preeclampsia. Our findings indicate substantial placental cellular heterogeneity in preeclampsia that predict previously observed bulk gene expression differences. Our deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.
Project description:Placental Fusobacterium nucleatum localization may be associated with pregnancy complications, including preeclampsia (PE), but nothing is known about its specific pathobiology. We aimed to perform transcriptomic analysis of the placentas of mice that were orally gavaged with Fusobacterium nucleatum or saline during pregnancy to further elucidate placental dysfunction in these conditions.
Project description:Preeclampsia (PE) and Intrauterine Growth Restriction (IUGR) are major contributor of perinatal morbility and mortality, these pregnancy disorders associated with placental ischemia and share many similar pathophysiological features. The aim of this study was to compare the placental gene expression profiles including mRNA and lnRNAs from pregnant women from four study groups; PE, IUGR, PE-IUGR and normal pregnancy (NP). Gene expression microarray analysis was performed on placental tissue obtained at the moment of delivery and results were validated using RTq-PCR. Differential gene expression analysis revealed that the largest transcript variation was observed in the IUGR samples compared to NP (n=461; 314 mRNAs: 252 up-regulated and 62 down-regulated) and 133 lncRNAs: 36 up-regulated and 98 down-regulated). We also detected a group of differentially expressed transcripts shared between the PE and IUGR samples compared to NP (n=39), including 9 lncRNAs with a high correlation degree (P <0.05). Functional enrichment of these shared transcripts showed that cytokine signaling pathways, protein modification and regulation of JAK-STAT cascade are over-represented in both placental ischemic diseases. These findings contribute to the molecular characterization of placental ischemia showing common epigenetic regulation implicated in the pathophysiology of preeclampsia and Intrauterine Growth Restriction