Disrupted placental circadian clock networks drive preeclampsia pathogenesis: An integrative bioinformatic analysis of key hub genes and regulatory pathways

Mar 13, 2026Placenta

Disrupted daily rhythms in the placenta may contribute to preeclampsia through key genes and pathways

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Abstract

Thirty-three circadian genes were identified as differentially expressed in Early-Onset Preeclampsia (EOPE).

Ten central hub genes were found to be significantly dysregulated in EOPE, including TGFB1, SPP1, and NTRK2.
A specific uncoupling of the regulatory feedback loop within the core clock machinery was observed.
NTRK2 demonstrated exceptional diagnostic potential as a near-perfect classifier with an Area Under the Curve (AUC) of 0.99.
Key transcription factors FOXC1 and GATA2 were identified as important in the upstream analysis.
Clinically relevant interactions were revealed between the hub gene TGFB1 and the chronotherapeutic agents melatonin and aspirin.

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INTRODUCTION: Preeclampsia (PE), a severe hypertensive disorder of pregnancy, is associated with circadian rhythm disruption, but the underlying placental molecular networks remain poorly understood. This study aimed to identify key hub genes, regulatory pathways, and novel biomarkers at the intersection of Early-Onset PE (EOPE) and the placental circadian clock.

METHODS: The placental transcriptomic dataset GSE114691 (20 EOPE vs. 20 gestational age-matched preterm controls) was analyzed to identify differentially expressed circadian genes (DECGs). Hub genes were prioritized via protein-protein interaction (PPI) networks. Hub gene expression was validated using effect size (Cohen's d) analysis, and diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) curve analysis. An upstream TF-miRNA co-regulatory network and drug-gene interactions were also analyzed.

RESULTS: This pipeline identified 33 DECGs and 10 central hub genes (TGFB1, SPP1, ENG, CD63, SNAI1, GPT2, APLN, EZR, NTRK2, and GLUD1), all significantly dysregulated in EOPE. Crucially, analysis of the core clock machinery revealed a specific uncoupling of the regulatory feedback loop. ROC analysis revealed exceptional diagnostic potential. Notably, NTRK2 emerged as a novel, near-perfect classifier (Area Under the Curve [AUC] = 0.99), outperforming the established marker ENG (AUC = 0.97). Upstream analysis identified key transcription factors (FOXC1, GATA2), and drug-gene analysis revealed clinically relevant interactions between TGFB1 and the chronotherapeutic agents melatonin and aspirin.

DISCUSSION: This study provides a systems-level map of the disrupted placental circadian network in EOPE. Our findings suggest that circadian misalignment is a central feature of placental pathology, offering a molecular rationale for developing novel chronotherapeutic strategies.

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Disrupted placental circadian clock networks drive preeclampsia pathogenesis: An integrative bioinformatic analysis of key hub genes and regulatory pathways

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