鉴定与特发性肺动脉高压免疫浸润和药物相互作用相关的关键转录因子和 miRNA 共同调控网络。

Identifying key transcription factors and miRNAs coregulatory networks associated with immune infiltrations and drug interactions in idiopathic pulmonary arterial hypertension.

机构信息

Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China.

Department of Pharmacy, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China.

出版信息

Math Biosci Eng. 2023 Jan;20(2):4153-4177. doi: 10.3934/mbe.2023194. Epub 2022 Dec 21.

DOI:10.3934/mbe.2023194

PMID:36899621

Abstract

BACKGROUND

The deregulated genetic factors are critically associated with idiopathic pulmonary arterial hypertension (IPAH) development and progression. However, the identification of hub-transcription factors (TFs) and miRNA-hub-TFs co-regulatory network-mediated pathogenesis in IPAH remains lacking.

METHODS

We used GSE48149, GSE113439, GSE117261, GSE33463, and GSE67597 for identifying key genes and miRNAs in IPAH. We used a series of bioinformatics approaches, including R packages, protein-protein interaction (PPI) network, and gene set enrichment analysis (GSEA) to identify the hub-TFs and miRNA-hub-TFs co-regulatory networks in IPAH. Also, we employed a molecular docking approach to evaluate the potential protein-drug interactions.

RESULTS

We found that 14 TFs encoding genes, including ZNF83, STAT1, NFE2L3, and SMARCA2 are upregulated, and 47 TFs encoding genes, including NCOR2, FOXA2, NFE2, and IRF5 are downregulated in IPAH relative to the control. Then, we identified the differentially expressed 22 hub-TFs encoding genes, including four upregulated (STAT1, OPTN, STAT4, and SMARCA2) and 18 downregulated (such as NCOR2, IRF5, IRF2, MAFB, MAFG, and MAF) TFs encoding genes in IPAH. The deregulated hub-TFs regulate the immune system, cellular transcriptional signaling, and cell cycle regulatory pathways. Moreover, the identified differentially expressed miRNAs (DEmiRs) are involved in the co-regulatory network with hub-TFs. The six hub-TFs encoding genes, including STAT1, MAF, CEBPB, MAFB, NCOR2, and MAFG are consistently differentially expressed in the peripheral blood mononuclear cells of IPAH patients, and these hub-TFs showed significant diagnostic efficacy in distinguishing IPAH cases from the healthy individuals. Moreover, we revealed that the co-regulatory hub-TFs encoding genes are correlated with the infiltrations of various immune signatures, including CD4 regulatory T cells, immature B cells, macrophages, MDSCs, monocytes, Tfh cells, and Th1 cells. Finally, we discovered that the protein product of STAT1 and NCOR2 interacts with several drugs with appropriate binding affinity.

CONCLUSIONS

The identification of hub-TFs and miRNA-hub-TFs co-regulatory networks may provide a new avenue into the mechanism of IPAH development and pathogenesis.

摘要

背景

失调的遗传因素与特发性肺动脉高压（IPAH）的发展和进展密切相关。然而，在 IPAH 中，识别枢纽转录因子（TFs）和 miRNA-枢纽-TFs 共同调节网络介导的发病机制仍然缺乏。

方法

我们使用 GSE48149、GSE113439、GSE117261、GSE33463 和 GSE67597 来识别 IPAH 中的关键基因和 miRNA。我们使用了一系列生物信息学方法，包括 R 包、蛋白质-蛋白质相互作用（PPI）网络和基因集富集分析（GSEA）来识别 IPAH 中的枢纽-TFs 和 miRNA-枢纽-TFs 共同调节网络。此外，我们还采用了分子对接方法来评估潜在的蛋白质-药物相互作用。

结果

我们发现，与对照组相比，在 IPAH 中，有 14 个编码 TFs 的基因（包括 ZNF83、STAT1、NFE2L3 和 SMARCA2）上调，有 47 个编码 TFs 的基因（包括 NCOR2、FOXA2、NFE2 和 IRF5）下调。然后，我们确定了 22 个差异表达的枢纽-TFs 编码基因，包括 4 个上调（STAT1、OPTN、STAT4 和 SMARCA2）和 18 个下调（如 NCOR2、IRF5、IRF2、MAFB、MAFG 和 MAFB）TFs 编码基因在 IPAH 中。失调的枢纽-TFs 调节免疫系统、细胞转录信号和细胞周期调节途径。此外，鉴定的差异表达 miRNA（DEmiRs）参与与枢纽-TFs 的共调节网络。六个枢纽-TFs 编码基因，包括 STAT1、MAF、CEBPB、MAFB、NCOR2 和 MAFG，在 IPAH 患者的外周血单核细胞中持续差异表达，这些枢纽-TFs 在区分 IPAH 病例与健康个体方面表现出显著的诊断效果。此外，我们发现共调节枢纽-TFs 编码基因与各种免疫特征的浸润有关，包括 CD4 调节性 T 细胞、不成熟 B 细胞、巨噬细胞、MDSCs、单核细胞、Tfh 细胞和 Th1 细胞。最后，我们发现 STAT1 和 NCOR2 的蛋白产物与几种具有适当结合亲和力的药物相互作用。