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Abstract
Neutrophils are activated and extensively infiltrate blood vessels in preeclamptic women. To identify genes that contribute to neutrophil activation and infiltration, we analyzed the transcriptomes of circulating neutrophils from normal pregnant and preeclamptic women. Neutrophils were collected at 30 weeks’ gestation and RNA and DNA were isolated for RNA sequencing and 5-hydroxy-methylcytosine (5-hmC) sequencing as an index of dynamic changes in neutrophil DNA methylation. Women with normal pregnancy who went on to develop mild preeclampsia at term had the most uniquely expressed genes (697) with 325 gene ontology pathways upregulated, many related to neutrophil activation and function. Women with severe preeclampsia who delivered prematurely had few pathways up- or downregulated. Cluster analysis revealed that gene expression in women with severe preeclampsia was an inverse mirror image of gene expression in normal pregnancy, while gene expression in women who developed mild preeclampsia was remarkably different from both. DNA methylation marks, key regulators of gene expression, are removed by the action of ten-eleven translocation (TET) enzymes, which oxidize 5-methylcytosines (5mCs), resulting in locus-specific reversal of DNA methylation. DNA sequencing for 5-hmC revealed no differences among the three groups. Genome-wide DNA methylation revealed extremely low levels in circulating neutrophils suggesting they are de-methylated. Collectively, these data demonstrate that neutrophil gene expression profiles can distinguish different preeclampsia phenotypes, and in the case of mild preeclampsia, alterations in gene expression occur well before clinical symptoms emerge. These findings serve as a foundation for further evaluation of neutrophil transcriptomes as biomarkers of preeclampsia phenotypes. Changes in DNA methylation in circulating neutrophils do not appear to mediate differential patterns of gene expression in either mild or severe preeclampsia.
Highlights
Preeclampsia (PE) is a hypertensive disorder of human pregnancy that affects multiple maternal organs, placental function and, consequentially, fetal physiology
Genes downregulated in normal pregnancy (NP) were upregulated in severe preeclampsia (SPE), whereas genes upregulated in NP were downregulated in SPE
Our findings demonstrate that neutrophil gene expression profiles can distinguish different PE phenotypes
Summary
Preeclampsia (PE) is a hypertensive disorder of human pregnancy that affects multiple maternal organs, placental function and, consequentially, fetal physiology. It occurs in 5–7% of all pregnancies, and is a leading cause of maternal and fetal morbidity and mortality [1]. The most significant differences in DNA methylation were “hypomethylated” genes in preeclamptic women and gene pathway analysis revealed significant interconnectivity of hypomethylated genes with innate immune function. Many of these genes encoded neutrophil-related molecules and proteases, such as matrix metalloproteinase-1 (MMP-1), neutrophil elastase, TNFα, and thromboxane synthase [5]. The dominance of hypomethylated genes related to inflammation in blood vessels of preeclamptic women is quite remarkable and suggests that epigenetic alterations play an important role in the pathology
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