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Clin Epigenetics. 2018 Mar 2;10:28. doi: 10.1186/s13148-018-0463-6. eCollection 2018.

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia.

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1Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON Canada.
2BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, BC Canada.
3Department of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC Canada.
4Interdisciplinary School of Health Sciences, University of Ottawa, 25 University Private, Ottawa, ON Canada.
5Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON Canada.
6Department of Obstetrics and Gynecology, University of Toronto, 23 Edward Street, Toronto, ON Canada.



Preeclampsia (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.


We 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.


Overall, 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.


Clustering; DNA methylation; Gene expression; Placenta; Preeclampsia; Subtypes

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Conflict of interest statement

Ethics approval was granted from the Research Ethics Boards of Mount Sinai Hospital (#13-0211-E), the University of Toronto (#29435), and the Ottawa Health Science Network (#2011623-01H). All women provided written informed consent for the collection of biological specimens and medical information.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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