Data_Sheet_1_Hypoxia- and Inflammation-Related Transcription Factor SP3 May Be Involved in Platelet Activation and Inflammation in Intracranial Hemorrhage.DOC

The purpose of this study was to identify the biomarkers implicated in the development of intracranial hemorrhage (ICH) and potential regulatory pathways. In the transcriptomic data for patients with ICH, we identified DEmiRNAs and DEmRNAs related to hypoxia, inflammation, and their transcription factors (TFs). An ICH-based miRNA-TF-mRNA regulatory network was thus constructed, and four biomarkers (TIMP1, PLAUR, DDIT3, and CD40) were screened for their association with inflammation or hypoxia by machine learning. Following this, SP3 was found to be a transcription factor involved in hypoxia and inflammation, which regulates TIMP1 and PLAUR. From the constructed miRNA-TF-mRNA regulatory network, we identified three axes, hsa-miR-940/RUNX1/TIMP1, hsa-miR-571/SP3/TIMP1, and hsa-miR-571/SP3/PLAUR, which may be involved in the development of ICH. Upregulated TIMP1 and PLAUR were validated in an independent clinical cohort 3 days after ICH onset. According to Gene Set Enrichment Analysis (GSEA), SP3 was discovered to be important in interleukin signaling and platelet activation for hemostasis. Transcription factor SP3 associated with hypoxia or inflammation plays an important role in development of ICH. This study provides potential targets for monitoring the severity of inflammation and hypoxia in patients with ICH.

本研究旨在明确与颅内出血（intracranial hemorrhage, ICH）发生发展相关的生物标志物及潜在调控通路。针对ICH患者的转录组数据，我们筛选出与缺氧、炎症及其转录因子（transcription factors, TFs）相关的差异表达miRNA（DEmiRNAs）与差异表达mRNA（DEmRNAs）。据此构建了基于ICH的miRNA-转录因子-mRNA调控网络，并通过机器学习筛选出4个与炎症或缺氧相关的生物标志物：TIMP1、PLAUR、DDIT3及CD40。后续研究发现，转录因子SP3参与缺氧与炎症过程，可调控TIMP1与PLAUR的表达。从构建的miRNA-转录因子-mRNA调控网络中，我们鉴定出3条可能参与ICH发生发展的调控轴：hsa-miR-940/RUNX1/TIMP1、hsa-miR-571/SP3/TIMP1以及hsa-miR-571/SP3/PLAUR。在独立临床队列中，我们验证了ICH发病3天后TIMP1与PLAUR的表达水平显著上调。通过基因集富集分析（Gene Set Enrichment Analysis, GSEA），我们发现SP3在白细胞介素信号通路及止血相关的血小板活化过程中发挥重要作用。综上，与缺氧或炎症相关的转录因子SP3在ICH的发生发展中具有关键调控作用。本研究为监测ICH患者的炎症与缺氧严重程度提供了潜在靶点。