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

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.

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

“…Our group recently uncovered characteristic placental transcriptomic changes and identified distinct gene modules and their hub transcription factors that are involved in the development of maternal or fetal disease conditions associated with preterm preeclampsia [57]. We found that many of these hub transcription factors and their target genes were predominantly expressed by villous trophoblasts, supporting their central role in the development of preeclampsia.…”

“…Earlier, we showed the enrichment of PPE genes among differentially expressed genes in the placenta in preterm preeclampsia [57,88]. Herein, we investigated how these PPE genes are involved in villous trophoblast functions and differentiation, and whether their villous trophoblastic dysregulation may have pathologic significance in preterm preeclampsia.…”

“…Herein, we investigated how these PPE genes are involved in villous trophoblast functions and differentiation, and whether their villous trophoblastic dysregulation may have pathologic significance in preterm preeclampsia. To identify PPE genes, we first mined BioGPS microarray and published data [15,17,57,89]. Among the 164 genes that met our stringent criteria (Table S1), 13 genes encode transcription regulatory proteins while 151 encode their potential targets.…”

“…Preeclampsia, a life-threatening obstetrical syndrome related to placental dysfunction [32,[57][58][59][60][61][62][63][64][65], is associated with dysregulated expression or function of many PPE proteins (e.g., CGB, LEP), transcription factors (e.g., GCM1, ESRRG), and signaling and kinase pathways (e.g., ERK1/2, p38), especially when it develops preterm [19,57,[66][67][68][69][70][71][72][73][74][75]. Based on the observations that the volume [76] and cellular architecture [67][68][69][77][78][79] of villous trophoblasts are severely impacted in preterm preeclampsia, it has been proposed that either the entire cytotrophoblast differentiation program [80], or particularly syncytialization [81][82][83][84][85][86][87], are affected in preterm preeclampsia, although neither have been proven at the systems level yet.…”

Risk of preeclampsia in patients with genetic predisposition to common medical conditions: a case-control study

“…Distinct molecular subtypes of PE that go beyond the distinction of early vs. late-onset disease are emerging [99][100][101] . While much work remains to define these subtypes, our analysis suggests clustering of different trait associations within the broad categories of early vs. late-onset.…”