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Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.

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cam.issuedOnline2018-08-08
dc.contributor.authorThan, Nandor Gabor
dc.contributor.authorRomero, Roberto
dc.contributor.authorTarca, Adi Laurentiu
dc.contributor.authorKekesi, Katalin Adrienna
dc.contributor.authorXu, Yi
dc.contributor.authorXu, Zhonghui
dc.contributor.authorJuhasz, Kata
dc.contributor.authorBhatti, Gaurav
dc.contributor.authorLeavitt, Ron Joshua
dc.contributor.authorGelencser, Zsolt
dc.contributor.authorPalhalmi, Janos
dc.contributor.authorChung, Tzu Hung
dc.contributor.authorGyorffy, Balazs Andras
dc.contributor.authorOrosz, Laszlo
dc.contributor.authorDemeter, Amanda
dc.contributor.authorSzecsi, Anett
dc.contributor.authorHunyadi-Gulyas, Eva
dc.contributor.authorDarula, Zsuzsanna
dc.contributor.authorSimor, Attila
dc.contributor.authorEder, Katalin
dc.contributor.authorSzabo, Szilvia
dc.contributor.authorTopping, Vanessa
dc.contributor.authorEl-Azzamy, Haidy
dc.contributor.authorLaJeunesse, Christopher
dc.contributor.authorBalogh, Andrea
dc.contributor.authorSzalai, Gabor
dc.contributor.authorLand, Susan
dc.contributor.authorTorok, Olga
dc.contributor.authorDong, Zhong
dc.contributor.authorKovalszky, Ilona
dc.contributor.authorFalus, Andras
dc.contributor.authorMeiri, Hamutal
dc.contributor.authorDraghici, Sorin
dc.contributor.authorHassan, Sonia S
dc.contributor.authorChaiworapongsa, Tinnakorn
dc.contributor.authorKrispin, Manuel
dc.contributor.authorKnöfler, Martin
dc.contributor.authorErez, Offer
dc.contributor.authorBurton, Graham J
dc.contributor.authorKim, Chong Jai
dc.contributor.authorJuhasz, Gabor
dc.contributor.authorPapp, Zoltan
dc.contributor.orcidBurton, Graham [0000-0001-8677-4143]
dc.date.accessioned2018-11-22T00:30:33Z
dc.date.available2018-11-22T00:30:33Z
dc.date.issued2018
dc.description.abstractPreeclampsia 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.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.32940
dc.identifier.eissn1664-3224
dc.identifier.issn1664-3224
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285586
dc.languageeng
dc.language.isoeng
dc.publisherFrontiers Media SA
dc.publisher.urlhttp://dx.doi.org/10.3389/fimmu.2018.01661
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectinflammation
dc.subjectischemia
dc.subjectliquid biopsy
dc.subjectomics
dc.subjectplacenta
dc.subjectpregnancy
dc.subjectsystems biology
dc.subjecttrophoblast invasion
dc.subjectAdult
dc.subjectBiomarkers
dc.subjectFemale
dc.subjectHumans
dc.subjectPlacenta Diseases
dc.subjectPre-Eclampsia
dc.subjectPregnancy
dc.subjectProteomics
dc.subjectSystems Biology
dc.subjectTrophoblasts
dc.titleIntegrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.
dc.typeArticle
dcterms.dateAccepted2018-07-04
prism.publicationDate2018
prism.publicationNameFront Immunol
prism.startingPage1661
prism.volume9
rioxxterms.licenseref.startdate2018-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3389/fimmu.2018.01661

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