Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

Abstract

BackgroundPreeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. We hypothesized that this heterogeneity is due to the existence of multiple subtypes of PE and, in support of this hypothesis, we recently identified five clusters of placentas within a large gene expression microarray dataset (N = 330), of which four (clusters 1, 2, 3, and 5) contained a substantial number of PE samples. However, while transcriptional analysis of placentas can subtype patients, we propose that the addition of epigenetic information could discern gene regulatory mechanisms behind the distinct PE pathologies, as well as identify clinically useful potential biomarkers.ResultsWe subjected 48 of our samples from transcriptional clusters 1, 2, 3, and 5 to Infinium HumanMethylation450 arrays. Samples belonging to transcriptional clusters 1–3 still showed visible relationships to each other by methylation, but cluster 5, with known chromosomal abnormalities, no longer formed a cohesive group. Within transcriptional clusters 2 and 3, controlling for fetal sex and gestational age in the identification of differentially methylated sites, compared to the healthier cluster 1, dramatically reduced the number of significant sites, but increased the percentage that demonstrated a strong linear correlation with gene expression (from 5% and 2% to 9% and 8%, respectively). Locations exhibiting a positive relationship between methylation and gene expression were most frequently found in CpG open sea enhancer regions within the gene body, while those with a significant negative correlation were often annotated to the promoter in a CpG shore region. Integrated transcriptome and epigenome analysis revealed modifications in TGF-beta signaling, cell adhesion, oxidative phosphorylation, and metabolism pathways in cluster 2 placentas, and aberrations in antigen presentation, allograft rejection, and cytokine-cytokine receptor interaction in cluster 3 samples.ConclusionsOverall, we have established DNA methylation alterations underlying a portion of the transcriptional development of “canonical” PE in cluster 2 and “immunological” PE in cluster 3. However, a significant number of the observed methylation changes were not associated with corresponding changes in gene expression, and vice versa, indicating that alternate methods of gene regulation will need to be explored to fully comprehend these PE subtypes.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0463-6) contains supplementary material, which is available to authorized users.

The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology

“…An additional fifth group of PE patients was also discovered in this clustering analysis, with no strong clinical, gene enrichment, or epigenetic 26 associations (cluster 5). Further investigation determined this cluster to be the likely result of chromosomal abnormalities related to confined placental mosaicism and not necessarily a distinct gene expressionebased subtype of PE.…”

Identification and characterization of methylation-mediated transcriptional dysregulation dictate methylation roles in preeclampsia

“…Both the gene expression (GSE75010) and methylation array (GSE98224) data for these 48 placentas are available. The detailed information could be found in previous published studies [38,39]. Probe ID information Affymetrix Human Gene 1.0 ST Array was downloaded from platform GPL6244 (https://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GPL19184).…”

Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia

“…38,51 Specifically, within a large cohort of 330 placentas that represented a wide range of preeclampsia clinical presentations and co-occurring complications (SGA, chronic hypertension [CH], and preterm labor), clustering revealed 5 patient groups based solely on placental gene expression, which included 4 subtypes of preeclampsia samples within clusters 1, 2, 3, and 5 (cluster 4 was composed almost exclusively of preterm control placentas with chorioamnionitis). 38 Using a combined transcriptional, 38 clinical, 38 epigenetic, 52 and histopathologic 53 approach, we have further described each of these distinct preeclampsia placental subtypes: cluster 1 preeclampsia samples demonstrated molecular similarity to healthy term control placentas and very little placental disease, which suggests that this may be a predominately "maternal" preeclampsia subtype that is driven by preexisting, subclinical, maternal cardiovascular disease; cluster 2 preeclampsia was termed "canonical", with overwhelming evidence of maternal vascular malperfusion and placental hypoxia; cluster 3 contained a less prevalent "immunologic" subtype of preeclampsia that was marked by signs of heightened immune response at the maternal-fetal interface, similar to an allograft rejection; 30,31 and, finally, a subtype of preeclamptic placentas with chromosomal abnormalities, but no other strong clinical, epigenetic, or histologic association, was discovered in cluster 5. Notably, patients with both maternal hypertension (preeclampsia or CH) and SGA split across all 4 of these clusters.…”