Integrative genomic and functional analysis identifies BCL10 as a novel driver of trophoblast senescence in preeclampsia.

Abstract

Objective: To identify senescence-driving genes causally linked to preeclampsia (PE) and to elucidate impact on placental dysfunction.

Methods: Placental RNA-seq data set GSE234729 was analyzed for differentially expressed genes. Weighted gene co-expression network analysis was used to extract aging-related genes (ARGEs) in PE. Mendelian randomization (MR) with eQTLs from GTEx prioritized candidate genes. In vitro validation employed HTR-8/SVneo cells exposed to 100 μM H2O2 as a senescence model, and functional verification was conducted through BCL10 overexpression or silencing. Senescence was quantified by SA-β-gal staining and aging-related proteins, invasion by Transwell assays, migration by Scratch assays. BCL10-silenced cells underwent transcriptome analysis.

Results: Integrating GSE234729 dataset, we identified 1488 differentially expressed genes and 1649 WGCNA hub genes, yielding 39 aging-related genes. MR pinpointed BCL10 as a risk factor for PE. PE placental tissues of patients and H2O2-treated HTR-8/SVneo cells showed significantly trophoblast senescence. BCL10 was significantly upregulated in PE, accompanied by the upregulation of senescence markers P62 and MMP3, and associated with body mass index (BMI) at delivery. Functionally, BCL10 overexpression increased P53/P21/P16, decreased Lamin B1, enhanced SA-β-gal activity, and inhibited invasion, while siRNA-mediated knockdown reversed these changes. BCL10 silencing in HTR-8/SVneo cells alters expression of 722 genes enriched in immune-inflammatory responses, apoptosis, and pathways including NF-κB and NOD-like receptor signaling.

Conclusions: BCL10 emerges as a causal, pro-senescence factor in PE that impairs trophoblast dysfunction. Targeting BCL10 may offer a novel strategy to alleviate placental aging-related complications in PE.