DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia

Abstract

Preeclampsia and intrauterine growth restriction (IUGR) are two of the most common adverse pregnancy outcomes, but their underlying causes are mostly unknown. Although multiple studies have investigated gene expression changes in these disorders, few studies have examined epigenetic changes. Analysis of the DNA methylation pattern associated with such pregnancies provides an alternative approach to identifying cellular changes involved in these disorders. We analyzed methylation of 1505 CpG sites associated with 807 genes in 26 placentas from early-onset preeclampsia (EOPET), late-onset preeclampsia, IUGR and control subjects using an Illumina GoldenGate Methylation panel. Thirty-four loci were hypomethylated (false discovery rate o10% and methylation difference 410%) in the early-onset preeclamptic placentas while no and only five differentially methylated loci were found in late-onset preeclamptic and IUGR placentas, respectively. Hypomethylation of 4 loci in EOPET was further confirmed by bisulfite pyrosequencing of 26 independent placental samples. The promoter of TIMP3 was confirmed to be significantly hypomethylated in EOPET placentas (P¼0.00001). Our results suggest that gene-specific hypomethylation may be a common phenomenon in EOPET placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET.

TLR9 Provokes Inflammation in Response to Fetal DNA: Mechanism for Fetal Loss in Preterm Birth and Preeclampsia

“…Fetal DNA is hypomethylated, and because TLR9 senses hypomethylated DNA normally found in abundance in microbial DNA, we hypothesized that it might sense fetal DNA and provoke an inflammatory reaction possibly leading to PTB (21). In this study, we report that human fetal DNA can indeed activate TLR9 in vitro.…”

The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1)

“…29 The parent-of-origin imprinting of many genes in placenta is likely to play key roles in various aspects of placental function, including trophoblast cell proliferation, differentiation, angiogenesis and transportation of nutrients. [30][31][32] Deletion of H19 gene and the H19/Igf2-imprinting control region (also known as H19 DMD) leads to increased levels of Igf2 and fetal overgrowth as well as hyperplasia of all layers in the placenta. 33 It has long been suggested that the increase in placenta weight in these knockout mice results from the doubling of all Igf2 transcripts.…”

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

“…It has also been shown previously that the methylation pattern of many genes differ between placentas from women with PE compared to controls. 36 In addition to ACOX2, we identified nine other genes whose transcription levels were correlated to both PE status and lipid levels ( Table 2). Even though these show lower statistical significance compared with ACOX2, we cannot exclude any of these genes from being as important in relation to developing both PE and CVD.…”