Landscape of Dysregulated Placental RNA Editing Associated With Preeclampsia

Yang, Xiaoxue; Yang, Jing; Liang, Xiaozhen; Chen, Qian; Jiang, Sijia; Liu, Haihua; Gao, Yue; Ren, Zhonglu; Shi, Yi‐Wu; Li, Sheng; Yu, Yang; Zhong, Ming; Yang, Xinping

doi:10.1161/hypertensionaha.120.14756

Cited by 17 publications

(27 citation statements)

References 85 publications

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“…The cyan module contained 486 genes ( Figure S1B ) and gene ontology analysis indicated a strong association with inflammation ( Figure 1B; Table 3 ). The cyan module was also strongly preserved in an independent dataset 41 ( Figure S1C ). Several well characterized inflammation-related genes were present in the module including members of the tumor necrosis factor ( TNFRSF11A, TNFAIP8L2, TNFRSF21, TNFSF13, TNFSF9 ) and interleukin ( IL2RA, IL12RB2, IL1RL1 ) families, as well as several genes associated with the myeloid lineage ( AIF1, CSF1, CD33, CD163 ).…”

Section: Resultsmentioning

confidence: 88%

“…We tested our modules for preservation in an independent dataset, GSE148241 41 , which included 41 placenta samples (9 with early-onset severe preeclampsia and 32 healthy controls). Only the 32 healthy control samples were extracted for use in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…As per the recommended thresholds we defined ܼ ௦௨௬ < 2 as no evidence of preservation, 2< ܼ ௦௨௬ < 10 as weak to moderate evidence of preservation and ܼ ௦௨௬ > 10 as strong evidence of preservation 40 . We tested our modules for preservation in an independent dataset, GSE148241 41 , which included 41 placenta samples (9 with early-onset severe preeclampsia and 32 healthy controls). Only the 32 healthy control samples were extracted for use in the analysis.…”

Section: Wgcnamentioning

confidence: 99%

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Homeostatic inflammation in the placenta is protective against adult cardiovascular and depressive outcomes

Fitzgerald

Shen

Yong

et al. 2023

Preprint

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Pathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an expression signature of homeostatic inflammation in the term placenta and use expression quantitative trait loci (eQTLs) to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we carried out a phenome-wide association study, followed by mendelian randomization and identified protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth were also over-represented within the module. Our data support a model where disruption of placental homeostatic inflammation, following preterm birth or intra-amniotic infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals. Finally, we identify aspirin as a putative modulator of this homeostatic inflammatory signature.

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Section: Resultsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Wgcnamentioning

confidence: 99%

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Homeostatic inflammation in the placenta is protective against adult cardiovascular and depressive outcomes

Fitzgerald

Shen

Yong

et al. 2023

Preprint

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“…Clinically established and previously suggested biomarkers By reanalyzing publicly available RNA-seq data from four different preeclampsia studies using our multistudy approach (the analysis of DEGs in the context of preeclampsia was not the primary focus in any of the studies included [33][34][35][36]), we were able to identify genes encoding the clinically established preeclampsia biomarker sFlt-1 (commonly used in combination with PlGF [25]), the previously suggested biomarker candidates sTREM-1 [27] and fibronectin [26], as well as several additional biomarker candidates, many of which have not been mentioned in the context of preeclampsia before, or only marginally. A role for sFlt-1 in preeclampsia was already suggested in 1997, on the basis of studies of the antagonistic vascular endothelial growth factor (VEGF) [28], followed by further characterization [29,30].…”

Section: Biomarkers In Preeclampsiamentioning

confidence: 99%

Biomarker screening in preeclampsia: an RNA-sequencing approach based on data from multiple studies

Rezk¹,

Grasegger²,

Brandstetter³

et al. 2022

Journal of Hypertension

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Objective:Biomarkers have become important in the prognosis and diagnosis of various diseases. High-throughput methods, such as RNA sequencing facilitate the detection of differentially expressed genes (DEGs), hence potential biomarker candidates. Individual studies suggest long lists of DEGs, hampering the identification of clinically relevant ones. Concerning preeclampsia – a major obstetric burden with high risk for adverse maternal and/or neonatal outcomes – limitations in diagnosis and prediction are still important issues. We, therefore, developed a workflow to facilitate the screening for biomarkers.Methods:On the basis of the tool DESeq2, a comprehensive workflow for identifying DEGs was established, analyzing data from several publicly available RNA-sequencing studies. We applied it to four RNA-sequencing datasets (one blood, three placenta) analyzing patients with preeclampsia and normotensive controls. We compared our results with other published approaches and evaluated their performance.Results:We identified 110 genes that are dysregulated in preeclampsia, observed in at least three of the studies analyzed, six even in all four studies. These included FLT-1, TREM-1, and FN1, which either represent established biomarkers at protein level, or promising candidates based on recent studies. For comparison, using a published meta-analysis approach, 5240 DEGs were obtained.Conclusion:This study presents a data analysis workflow for preeclampsia biomarker screening, capable of identifying promising biomarker candidates, while drastically reducing the numbers of candidates. Moreover, we were also able to confirm its performance for heart failure. This approach can be applied to additional diseases for biomarker identification, and the set of DEGs identified in preeclampsia represents a resource for further studies.

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“…Weighted gene correlation network analysis (WGCNA) is a data reduction technique applied widely in gene expression studies to identify and functionally categorize clusters of highly correlated transcripts (co-expression modules) 7 . The resulting clusters can then be related to clinical variables (e.g., blood pressure) using consolidation metrics such as "eigengenes" 8 , and "metagenes" 9 . Since modules thus constructed are impartial to clinical outcome, WGCNA can be applied when analyzing datasets with unknown sample stratifications.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics-Based Subphenotyping of the Human Placenta Enabled by Weighted Correlation Network Analysis in Early-Onset Preeclampsia With and Without Fetal Growth Restriction

et al. 2023

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Background: Placental disorders contribute to pregnancy complications, including preeclampsia and fetal growth restriction (FGR), but debate regarding their specific pathobiology persists. Our objective was to apply transcriptomics with weighted gene correlation network analysis to further clarify the placental dysfunction in these conditions. Methods: We performed RNA sequencing with weighted gene correlation network analysis using human placental samples (n=30), separated into villous tissue and decidua basalis, and clinically grouped as follows: (1) early-onset preeclampsia (EOPE)+FGR (n=7); (2) normotensive, nonanomalous preterm FGR (n=5); (2) EOPE without FGR (n=8); (4) spontaneous idiopathic preterm birth (n=5) matched for gestational age (GA); and (5) uncomplicated term births (n=5). Our data was compared with RNA sequencing data sets from public databases (GSE114691, GSE148241, and PRJEB30656; n=130 samples). Results: We identified 14 correlated gene modules in our specimens, of which most were significantly correlated with birthweight and maternal blood pressure. Of the 3 network modules consistently predictive of EOPE±FGR across data sets, we prioritized a coexpression gene group enriched for hypoxia-response and metabolic pathways for further investigation. Cluster analysis based on transcripts from this module and the glycolysis/gluconeogenesis metabolic pathway consistently distinguished a subset of EOPE±FGR samples with an expression signature suggesting modified tissue bioenergetics. We demonstrated that the expression ratios of LDHA / LDHB and PDK1 / GOT1 could be used as surrogate indices for the larger panels of genes in identifying this subgroup. Conclusions: We provide novel evidence for a molecular subphenotype consistent with a glycolytic metabolic shift that occurs more frequently but not universally in placental specimens of EOPE±FGR.

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Landscape of Dysregulated Placental RNA Editing Associated With Preeclampsia

Cited by 17 publications

References 85 publications

Homeostatic inflammation in the placenta is protective against adult cardiovascular and depressive outcomes

Homeostatic inflammation in the placenta is protective against adult cardiovascular and depressive outcomes

Biomarker screening in preeclampsia: an RNA-sequencing approach based on data from multiple studies

Transcriptomics-Based Subphenotyping of the Human Placenta Enabled by Weighted Correlation Network Analysis in Early-Onset Preeclampsia With and Without Fetal Growth Restriction

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