Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.
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Authors
Than, Nandor Gabor
Romero, Roberto
Tarca, Adi Laurentiu
Kekesi, Katalin Adrienna
Xu, Yi
Xu, Zhonghui
Juhasz, Kata
Bhatti, Gaurav
Leavitt, Ron Joshua
Gelencser, Zsolt
Palhalmi, Janos
Chung, Tzu Hung
Gyorffy, Balazs Andras
Orosz, Laszlo
Demeter, Amanda
Szecsi, Anett
Hunyadi-Gulyas, Eva
Darula, Zsuzsanna
Simor, Attila
Eder, Katalin
Szabo, Szilvia
Topping, Vanessa
El-Azzamy, Haidy
LaJeunesse, Christopher
Balogh, Andrea
Szalai, Gabor
Land, Susan
Torok, Olga
Dong, Zhong
Kovalszky, Ilona
Falus, Andras
Meiri, Hamutal
Draghici, Sorin
Hassan, Sonia S
Chaiworapongsa, Tinnakorn
Krispin, Manuel
Knöfler, Martin
Erez, Offer
Burton, Graham J
Kim, Chong Jai
Juhasz, Gabor
Papp, Zoltan
Publication Date
2018Journal Title
Front Immunol
ISSN
1664-3224
Publisher
Frontiers Media SA
Volume
9
Pages
1661
Language
eng
Type
Article
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Than, N. G., Romero, R., Tarca, A. L., Kekesi, K. A., Xu, Y., Xu, Z., Juhasz, K., et al. (2018). Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.. Front Immunol, 9 1661. https://doi.org/10.3389/fimmu.2018.01661
Abstract
Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.
Keywords
Trophoblasts, Humans, Pre-Eclampsia, Placenta Diseases, Proteomics, Systems Biology, Pregnancy, Adult, Female, Biomarkers
Identifiers
External DOI: https://doi.org/10.3389/fimmu.2018.01661
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285586
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