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Placental Gene Co-expression Network for Maternal Plasma Lipids Revealed Enrichment of Inflammatory Response Pathways.

ABSTRACT: Maternal dyslipidemia during pregnancy has been associated with suboptimal fetal growth and increased cardiometabolic diseasse risk in offspring. Altered placental function driven by placental gene expression is a hypothesized mechanism underlying these associations. We tested the relationship between maternal plasma lipid concentrations and placental gene expression. Among 64 pregnant women from the NICHD Fetal Growth Studies-Singleton cohort with maternal first trimester plasma lipids we extracted RNA-Seq on placental samples obtained at birth. Placental gene co-expression networks were validated by regulatory network analysis that integrated transcription factors and gene expression, and genome-wide transcriptome analysis. Network analysis detected 24 gene co-expression modules in placenta, of which one module was correlated with total cholesterol (r = 0.27, P-value = 0.03) and LDL-C (r = 0.31, P-value = 0.01). Genes in the module (n = 39 genes) were enriched in inflammatory response pathways. Out of the 39 genes in the module, three known lipid-related genes (MPO, PGLYRP1 and LTF) and MAGEC2 were validated by the regulatory network analysis, and one known lipid-related gene (ALX4) and two germ-cell development-related genes (MAGEC2 and LUZP4) were validated by genome-wide transcriptome analysis. Placental gene expression signatures associated with unfavorable maternal lipid concentrations may be potential pathways underlying later life offspring cardiometabolic traits. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00912132.

SUBMITTER: Ouidir M

PROVIDER: S-EPMC8567461 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Placental Gene Co-expression Network for Maternal Plasma Lipids Revealed Enrichment of Inflammatory Response Pathways.

Ouidir Marion M Chatterjee Suvo S Mendola Pauline P Zhang Cuilin C Grantz Katherine L KL Tekola-Ayele Fasil F

Frontiers in genetics 20211021

Maternal dyslipidemia during pregnancy has been associated with suboptimal fetal growth and increased cardiometabolic diseasse risk in offspring. Altered placental function driven by placental gene expression is a hypothesized mechanism underlying these associations. We tested the relationship between maternal plasma lipid concentrations and placental gene expression. Among 64 pregnant women from the NICHD Fetal Growth Studies-Singleton cohort with maternal first trimester plasma lipids we extra ...[more]

PMID: 34745199

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Project description:Obese pregnant women have increased levels of proinflammatory cytokines in maternal circulation and placental tissues. However, the pathways contributing to placental inflammation in obesity are largely unknown. We tested the hypothesis that maternal body mass index (BMI) was associated with elevated proinflammatory cytokines in maternal and fetal circulations and increased activation of placental inflammatory pathways. A total of 60 women of varying pre-/early pregnancy BMI, undergoing delivery by Cesarean section at term, were studied. Maternal and fetal (cord) plasma were collected for analysis of insulin, leptin, IL-1beta, IL-6, IL-8, monocyte chemoattractant protein (MCP) 1, and TNFalpha by multiplex ELISA. Activation of the inflammatory pathways in the placenta was investigated by measuring the phosphorylated and total protein expression of p38-mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK)-MAPK, signal transducer-activated transcription factor (STAT) 3, caspase-1, IL-1beta, IkappaB-alpha protein, and p65 DNA-binding activity. To determine the link between activated placental inflammatory pathways and elevated maternal cytokines, cultured primary human trophoblast (PHT) cells were treated with physiological concentrations of insulin, MCP-1, and TNFalpha, and inflammatory signaling analyzed by Western blot. Maternal BMI was positively correlated with maternal insulin, leptin, MCP-1, and TNFalpha, whereas only fetal leptin was increased with BMI. Placental phosphorylation of p38-MAPK and STAT3, and the expression of IL-1beta protein, were increased with maternal BMI; phosphorylation of p38-MAPK was also correlated with birth weight. In contrast, placental NFkappaB, JNK and caspase-1 signaling, and fetal cytokine levels were unaffected by maternal BMI. In PHT cells, p38-MAPK was activated by MCP-1 and TNFalpha, whereas STAT3 phosphorylation was increased following TNFalpha treatment. Maternal BMI is associated with elevated maternal cytokines and activation of placental p38-MAPK and STAT3 inflammatory pathways, without changes in fetal systemic inflammatory profile. Activation of p38-MAPK by MCP-1 and TNFalpha, and STAT3 by TNFalpha, suggests a link between elevated proinflammatory cytokines in maternal plasma and activation of placental inflammatory pathways. We suggest that inflammatory processes associated with elevated maternal BMI may influence fetal growth by altering placental function.

Project description:Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

Dataset Information

Placental Gene Co-expression Network for Maternal Plasma Lipids Revealed Enrichment of Inflammatory Response Pathways.

Publications

Placental Gene Co-expression Network for Maternal Plasma Lipids Revealed Enrichment of Inflammatory Response Pathways.

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