Comparison of immune-related gene signatures and immune infiltration features in early- and late-onset preeclampsia

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-02-16 DOI:10.1002/jgm.3676

Quanfeng Wu, Xiang Ying, Weiwei Yu, Huanxi Li, Wei Wei, Xueyan Lin, Meilin Yang, Xueqin Zhang

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Abstract

Background

Preeclampsia, a severe pregnancy syndrome, is widely accepted divided into early- and late-onset preeclampsia (EOPE and LOPE) based on the onset time of preeclampsia, with distinct pathophysiological origins. However, the molecular mechanism especially immune-related mechanisms for EOPE and LOPE is currently obscure. In the present study, we focused on placental immune alterations between EOPE and LOPE and search for immune-related biomarkers that could potentially serve as potential therapeutic targets through bioinformatic analysis.

Methods

The gene expression profiling data was obtained from the Gene Expression Omnibus database. ESTIMATE algorithm and Gene Set Enrichment Analysis were employed to evaluate the immune status. The intersection of differentially expressed genes in GSE74341 series and immune-related genes set screened differentially expressed immune-related genes. Protein–protein interaction network and random forest were used to identify hub genes with a validation by a quantitative real-time PCR. Kyoto Encyclopedia of Genes and Genomes pathways, Gene Ontology and gene set variation analysis were utilized to conduct biological function and pathway enrichment analyses. Single-sample gene set enrichment analysis and CIBERSORTx tools were employed to calculate the immune cell infiltration score. Correlation analyses were evaluated by Pearson correlation analysis. Hub genes-miRNA network was performed by the NetworkAnalyst online tool.

Results

Immune score and stromal score were all lower in EOPE samples. The immune system-related gene set was significantly downregulated in EOPE compared to LOPE samples. Four hub differentially expressed immune-related genes (IL15, GZMB, IL1B and CXCL12) were identified based on a protein–protein interaction network and random forest. Quantitative real-time polymerase chain reaction validated the lower expression levels of four hub genes in EOPE compared to LOPE samples. Immune cell infiltration analysis found that innate and adaptive immune cells were apparent lacking in EOPE samples compared to LOPE samples. Cytokine-cytokine receptor, para-inflammation, major histocompatibility complex class I and T cell co-stimulation pathways were significantly deficient and highly correlated with hub genes. We constructed a hub genes-miRNA regulatory network, revealing the correlation between hub genes and hsa-miR-374a-5p, hsa-miR-203a-3p, hsa-miR-128-3p, hsa-miR-155-3p, hsa-miR-129-2-3p and hsa-miR-7-5p.

Conclusions

The innate and adaptive immune systems were severely impaired in placentas of EOPE. Four immune-related genes (IL15, GZMB, IL1B and CXCL12) were closely correlated with immune-related pathogenesis of EOPE. The result of our study may provide a new basis for discriminating between EOPE and LOPE and acknowledging the role of the immune landscape in the eventual interference and tailored treatment of EOPE.

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早期和晚期子痫前期免疫相关基因特征和免疫浸润特征的比较。

背景：子痫前期是一种严重的妊娠综合征，根据子痫前期的发病时间被广泛认为可分为早发型子痫前期和晚发型子痫前期（EOPE 和 LOPE），其病理生理起源各不相同。然而，EOPE 和 LOPE 的分子机制，尤其是免疫相关机制目前尚不清楚。在本研究中，我们重点研究了EOPE和LOPE的胎盘免疫改变，并通过生物信息学分析寻找可能作为潜在治疗靶点的免疫相关生物标志物：基因表达谱数据来自基因表达总库数据库。方法：基因表达谱数据来自基因表达总库，采用ESTIMATE算法和基因组富集分析法评估免疫状态。通过 GSE74341 系列差异表达基因与免疫相关基因集的交叉，筛选出差异表达的免疫相关基因。利用蛋白质-蛋白质相互作用网络和随机森林来识别枢纽基因，并通过定量实时 PCR 进行验证。利用《京都基因组百科全书》通路、基因本体和基因组变异分析进行生物功能和通路富集分析。利用单样本基因组富集分析和 CIBERSORTx 工具计算免疫细胞浸润得分。相关性分析通过皮尔逊相关分析进行评估。枢纽基因-miRNA网络由NetworkAnalyst在线工具完成：结果：EOPE样本的免疫评分和基质评分均较低。与LOPE样本相比，EOPE样本中免疫系统相关基因组明显下调。根据蛋白-蛋白相互作用网络和随机森林，确定了四个差异表达的免疫相关基因（IL15、GZMB、IL1B 和 CXCL12）。定量实时聚合酶链反应验证了与 LOPE 样本相比，四个中心基因在 EOPE 中的表达水平较低。免疫细胞浸润分析发现，与 LOPE 样本相比，EOPE 样本明显缺乏先天性和适应性免疫细胞。细胞因子-细胞因子受体、副炎症、主要组织相容性复合体 I 类和 T 细胞协同刺激通路明显缺乏，且与中枢基因高度相关。我们构建了一个中心基因-miRNA调控网络，揭示了中心基因与hsa-miR-374a-5p、hsa-miR-203a-3p、hsa-miR-128-3p、hsa-miR-155-3p、hsa-miR-129-2-3p和hsa-miR-7-5p之间的相关性：结论：EOPE胎盘中的先天性免疫系统和适应性免疫系统严重受损。4个免疫相关基因（IL15、GZMB、IL1B和CXCL12）与EOPE的免疫相关发病机制密切相关。我们的研究结果可为区分 EOPE 和 LOPE 提供新的依据，并确认免疫环境在最终干扰和有针对性地治疗 EOPE 中的作用。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.