Comprehensive Analysis of Preeclampsia-Associated DNA Methylation in the Placenta

Chu, Tianjiao; Bunce, Kimberly; Shaw, Patricia; Shridhar, Viji; Althouse, Andrew D.; Hubel, Carl A.; Peters, David

doi:10.1371/journal.pone.0107318

Cited by 75 publications

(69 citation statements)

References 44 publications

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“…DNA methylation is intimately linked to chromatin structure, genome function, and placental phenotype. Multiple reports exist of abnormal fetal epigenetic programing in mothers with gestational diabetes, nutritional deficiency, tobacco exposure, synthetic estrogens, and preeclampsia . To improve our understanding of how the maternal environment influences fetal programming, it is important to further our understanding of pregnancy‐specific epigenetic profiles both in the placental and maternal compartments.…”

Section: Discussionmentioning

confidence: 99%

High‐resolution analysis of the human placental DNA methylome in early gestation

et al. 2020

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Background/Objective We communicate high‐read‐depth bisulfite sequencing analysis of the chorionic villus (CV) DNA methylome from samples obtained between 11 and 13 weeks gestation and samples of gestationally age‐matched maternal blood cells (MBC). Methods This was achieved through solution‐phase targeted region capture (84 Mb) of bisulfite converted human DNA. Results We identified biphasic distribution of methylation in CV and MBC genomes. We found greater numbers of intermediate methylated sites (20%‐80% methylated) in CV and greater number of high methylation sites in MBC and investigated distributions of these in promoters, introns, exons, CpG islands, CpG islands shores, and enhancers. We identified differentially methylated sites distinguishing CV and MBC. These are less likely to occur in CpG islands (CGIs), particularly those that exist outside promoters, exons, and introns. We found that gene promoter and gene body methylation patterns are associated with mRNA transcriptional profiles in CV. Despite the relative hypomethylation of CV genomes, we found that these contain DM regions that are more likely to be hypermethylated in CV relative to MBC. Conclusions Our data provide novel insight into the structure and organization of the CV epigenome, which may inform future studies of placental biology and noninvasive prenatal phenotyping.

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Section: Discussionmentioning

confidence: 99%

High‐resolution analysis of the human placental DNA methylome in early gestation

et al. 2020

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“…[9][10][11]13 These epigenetic changes are believed to affect placental gene expression and in this way contribute to the pathophysiology of preeclampsia. However, specific molecules and cell types underlying placental DNA hypomethylation in preeclampsia remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…8 Initial studies determined that preeclampsia placentas are characterized by widespread DNA hypomethylation when compared with placental DNA from normotensive pregnancies. 9,10 Subsequent studies focused on CpG dinucleotide repeats (CpG islands) located in the promoter region of many genes. [11][12][13] DNA methylation at these promoter-specific CpG islands is frequently associated with the repression of gene expression, and conversely, hypomethylation is frequently associated with gene activation.…”

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confidence: 99%

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Huang

Iriyama

et al. 2017

Hypertension

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Consistent with this, detailed analysis of DNA from preeclampsia placentas showed that hypomethylation at specific promoter regions was associated with increased expression of specific genes that may contribute to the pathophysiology of Abstract-Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality.Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibodyinduced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation.Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. (Hypertension. 2017;70:209-218.

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“…Considering the role of different lncRNAs including H19, there is no surprise to investigate the possible effects of H19 polymorphisms and promoter methylation on the development and progression of PE . Moreover, according to several studies, the pathogenesis of PE is closely associated with the methylation status of relevant genes . Nevertheless, the reports of H19 promoter methylation on PE risk are rare .…”

Section: Introductionmentioning

confidence: 99%

The effects of placental long noncoding RNA H19 polymorphisms and promoter methylation on H19 expression in association with preeclampsia susceptibility

et al. 2019

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The effect of DNA methylation on gene expression triggered it as a susceptibility factor in various diseases including preeclampsia (PE). The pathogenesis of PE is closely associated with the methylation status and genetic variants of relevant genes. Therefore, the aim of the study was to investigate the possible impacts of the placental DNA methylation and rs3741219, rs217727, and rs2107425 polymorphisms of the H19 gene on the PE susceptibility as well as the its mRNA expression. Moreover, eight haplotypes of three loci in the H19 gene were analyzed. In this case‐control study, the placentas of 107 preeclamptic and 113 non‐preeclamptic women were collected after delivery. The methylation status was assessed by methylation‐specific polymerase chain reaction (PCR). The H19 polymorphisms were genotyped using polymerase chain reaction‐restriction fragment length polymorphism or amplification refractory mutation system‐polymerase chain reaction methods. The quantitative real time PCR was used for mRNA expression assay. The placental H19 rs3741219 and rs2107425 polymorphisms were not associated with PE. However, H19 rs217727CT and TT genotypes might be associated with a 9.2‐ and 17.7‐fold increased risk of PE, respectively. The Trs3741219 Crs217727 Crs2107425 and Trs3741219 Crs217727 Trs2107425 haplotypes were significantly lower, whereas the Trs3741219 Trs217727 Crs2107425 and Crs3741219 Trs217727 Crs2107425 haplotypes were significantly higher in PE women. Promoter but not upstream region hypermethylation of H19 gene could be led to decreased risk of PE (MM vs. UM + UU). No significant difference was observed in the placental mRNA expression between two groups. The H19 expression was significantly higher in women with unmethylated (UU), compared to methylated promoter (MM). The H19 expression was 17‐ and 15‐fold higher in H19‐rs2107425 CC and CT genotypes in PE women. In conclusion, the H19 rs2107425 polymorphism was associated with a higher risk of PE and increased H19 mRNA expression. The promoter hypermethylation of H19 gene was associated with a lower risk of PE and decreased H19 mRNA expression.

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Comprehensive Analysis of Preeclampsia-Associated DNA Methylation in the Placenta

Cited by 75 publications

References 44 publications

High‐resolution analysis of the human placental DNA methylome in early gestation

High‐resolution analysis of the human placental DNA methylome in early gestation

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

The effects of placental long noncoding RNA H19 polymorphisms and promoter methylation on H19 expression in association with preeclampsia susceptibility

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