Single-Cell Transcriptome Analysis Reveals the Importance of IRF1/FSTL1 in Synovial Fibroblast Subse

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Department of traumatic orthopedics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.

Department of Joint and Sports Medicine, Taian City Central Hospital, Taian City, Shandong, China.

Department of nuclear medicine, Taian City Central Hospital, Taian City, Shandong, China.

Objectives . This study aimed to investigate the potential role of synovial fibroblasts (SFs) in the development of rheumatoid arthritis (RA) to identify potential molecular targets and provide a theoretical basis for the treatment of RA. Methods . GSE109449, a fibroblast transcriptome dataset of synovial tissue from RA and osteoarthritis (OA), were obtained from the GEO database. After standard cell quality control, this single-cell transcriptome data was used to perform routine single-cell analysis processes. After completing dimensionality reduction, clustering, and cell subset identification of fibroblasts, the SCENIC analysis helped calculate the significant gene regulatory networks in fibroblasts and their subsets. From these computed gene regulatory networks, the regulon in which follistatin-like protein 1 (FSTL1) resides was extracted and used to analyze the transcriptional regulatory status of fibroblasts. Finally, the gene set enrichment analysis (GSEA) was used to calculate the respective enriched gene sets of IRF1 and FSTL1. Results . Three SF subgroups were identified from the single-cell transcriptome analysis; SF subset 3 was more abundant in RA than in OA ( ). From the SCENIC analysis, we obtained 269 regulons and the corresponding gene regulatory networks in SF from the RA datasets. Next, we screened and obtained a regulon-containing FSTL1, where IRF1 was the major transcription factor. The top five regulons in SF subset 3 were TWIST1, MECOM, KLF6, MAFB, and RUNX1. Among the 3 SF subsets, IRF1 regulon was ranked the highest in SF subset 3. Differential analysis of pseudobulk RNA-seq showed that IRF1 was up-regulated in RA compared to OA. Between the three SF subgroups, IRF1 and FSTL1 expression was more up-regulated in SF subset 3 compared to the other two subgroups. Conclusions . IRF1 was found to regulate the invasiveness of SFs by regulating FSTL1, which may influence the disease progression of RA. 中文翻译：目标。本研究旨在探讨滑膜成纤维细胞（SF）在类风湿性关节炎（RA）发生发展中的潜在作用，寻找潜在的分子靶点，为RA的治疗提供理论依据。方法。GSE109449 是 RA 和骨关节炎 (OA) 滑膜组织的成纤维细胞转录组数据集，从 GEO 数据库获得。经过标准细胞质量控制后，该单细胞转录组数据用于执行常规单细胞分析过程。在完成成纤维细胞的降维、聚类和细胞亚群识别后，SCENIC分析有助于计算成纤维细胞及其亚群中重要的基因调控网络。从这些计算的基因调控网络中，提取卵泡抑素样蛋白 1 (FSTL1) 所在的调控子，并用于分析成纤维细胞的转录调控状态。最后，利用基因集富集分析（GSEA）计算IRF1和FSTL1各自的富集基因集。结果。从单细胞转录组分析中鉴定出三个 SF 亚组；SF 子集 3 在 RA 中比在 OA 中更丰富（）。通过SCENIC分析，我们从RA数据集中获得了SF中的269个调节子和相应的基因调控网络。接下来，我们筛选并获得了含有调节子的FSTL1，其中IRF1是主要转录因子。SF 子集 3 中排名前五的调节子是 TWIST1、MECOM、KLF6、MAFB 和 RUNX1。在 3 个 SF 子集中，IRF1 调节子在 SF 子集 3 中排名最高。pseudobulk RNA-seq 的差异分析显示，与 OA 相比，IRF1 在 RA 中表达上调。在三个 SF 亚组之间，与其他两个亚组相比，SF 亚组 3 中 IRF1 和 FSTL1 的表达上调更多。结论。研究发现 IRF1 通过调节 FSTL1 来调节 SF 的侵袭性，从而可能影响 RA 的疾病进展。