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Background <p>Preeclampsia (PE), a life-threatening hypertensive disorder of pregnancy, remains poorly characterized at the post-transcriptional regulation level. While alternative splicing (AS) perturbations drive pathological processes in numerous diseases, their systematic investigation in PE pathogenesis is lacking.</p> Results <p>Through integrative analysis of placental RNA-seq data (<i>n</i> = 18; 9 early-onset severe PE vs. 9 controls) using SUVA-based splicing quantification and RBP interactome mapping, we identified 276 conserved regulated splicing events (PE-RAS) with dominant isoform usage (pSAR ≥ 50%, pvalue ≤ 0.05). These events disproportionately affected DNA damage response (DDR) pathways, particularly in <i>DYRK2</i> (Δsplicing ratio = 0.33, <i>p</i> = 2.8e-3) and <i>FZR1</i> (Δsplicing ratio = 0.23, <i>p</i> = 2.2e-4), whose aberrant splicing correlated with DNA repair function. Co-expression network analysis revealed 11 upregulated RNA-binding proteins (RBPs) (e.g., DUSP1, FLNB; FC &gt; 2, FDR &lt; 0.05) orchestrating DDR-associated splicing through sequence-specific interactions (|r| &gt;0.6, <i>p</i> &lt; 0.01). Strikingly, these RBP-AS axes coincided with immune microenvironment remodeling, manifesting as resting NK cells, resting memory CD4 + T-cell and Neutrophils cells depletion, potentially linking splicing dysregulation to maternal-fetal interface inflammation. Experimental validation confirmed RBPs overexpression (qRT–PCR) in PE placentas.</p> Conclusions <p>Our study establishes RBP-mediated splicing coordination as a novel regulatory layer connecting genomic instability and immune dyshomeostasis in PE, providing a framework for splicing-targeted therapeutic development.</p>

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Comprehensive analysis of RNA sequencing reveals DNA damage response and immune-associated alternative splicing and RBP regulators contributing to preeclampsia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • YanHua Wang,
  • WenXia Li,
  • ZhiHui Li,
  • KePing Qiang,
  • JiangYong Shen,
  • LiJuan Huang

摘要

Background

Preeclampsia (PE), a life-threatening hypertensive disorder of pregnancy, remains poorly characterized at the post-transcriptional regulation level. While alternative splicing (AS) perturbations drive pathological processes in numerous diseases, their systematic investigation in PE pathogenesis is lacking.

Results

Through integrative analysis of placental RNA-seq data (n = 18; 9 early-onset severe PE vs. 9 controls) using SUVA-based splicing quantification and RBP interactome mapping, we identified 276 conserved regulated splicing events (PE-RAS) with dominant isoform usage (pSAR ≥ 50%, pvalue ≤ 0.05). These events disproportionately affected DNA damage response (DDR) pathways, particularly in DYRK2 (Δsplicing ratio = 0.33, p = 2.8e-3) and FZR1 (Δsplicing ratio = 0.23, p = 2.2e-4), whose aberrant splicing correlated with DNA repair function. Co-expression network analysis revealed 11 upregulated RNA-binding proteins (RBPs) (e.g., DUSP1, FLNB; FC > 2, FDR < 0.05) orchestrating DDR-associated splicing through sequence-specific interactions (|r| >0.6, p < 0.01). Strikingly, these RBP-AS axes coincided with immune microenvironment remodeling, manifesting as resting NK cells, resting memory CD4 + T-cell and Neutrophils cells depletion, potentially linking splicing dysregulation to maternal-fetal interface inflammation. Experimental validation confirmed RBPs overexpression (qRT–PCR) in PE placentas.

Conclusions

Our study establishes RBP-mediated splicing coordination as a novel regulatory layer connecting genomic instability and immune dyshomeostasis in PE, providing a framework for splicing-targeted therapeutic development.