GenHotel, Univ. Évry, Université Paris-Saclay, 91025, Genopole, Évry, France.
University Lille, CNRS, Inserm, CHU Lille, Centre Oscar Lambret, UMR9020, UMR1277, Canther, Cancer Heterogeneity, Plasticity and Resistance To Therapies, 59000, Lille, France.
Sci Rep. 2020 Oct 1;10(1):16236. doi: 10.1038/s41598-020-73147-4.
Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects the synovial joints of the body. Rheumatoid arthritis fibroblast-like synoviocytes (RA FLS) are central players in the disease pathogenesis, as they are involved in the secretion of cytokines and proteolytic enzymes, exhibit invasive traits, high rate of self-proliferation and an apoptosis-resistant phenotype. We aim at characterizing transcription factors (TFs) that are master regulators in RA FLS and could potentially explain phenotypic traits. We make use of differentially expressed genes in synovial tissue from patients suffering from RA and osteoarthritis (OA) to infer a TF co-regulatory network, using dedicated software. The co-regulatory network serves as a reference to analyze microarray and single-cell RNA-seq data from isolated RA FLS. We identified five master regulators specific to RA FLS, namely BATF, POU2AF1, STAT1, LEF1 and IRF4. TF activity of the identified master regulators was also estimated with the use of two additional, independent software. The identified TFs contribute to the regulation of inflammation, proliferation and apoptosis, as indicated by the comparison of their differentially expressed target genes with hallmark molecular signatures derived from the Molecular Signatures Database (MSigDB). Our results show that TFs influence could be used to identify putative master regulators of phenotypic traits and suggest novel, druggable targets for experimental validation.
类风湿关节炎（RA）是一种全身性自身免疫性疾病，影响身体的滑膜关节。类风湿关节炎成纤维样滑膜细胞（RA FLS）是疾病发病机制的核心参与者，因为它们参与细胞因子和蛋白水解酶的分泌，表现出侵袭性特征、高自我增殖率和抗细胞凋亡表型。我们旨在描述 RA FLS 中作为主调控因子的转录因子（TFs），这些因子可能解释表型特征。我们利用来自患有类风湿关节炎和骨关节炎（OA）的患者的滑膜组织中差异表达的基因，使用专用软件推断 TF 共调控网络。该共调控网络可作为参考，用于分析从分离的 RA FLS 获得的微阵列和单细胞 RNA-seq 数据。我们确定了五个特定于 RA FLS 的主调控因子，即 BATF、POU2AF1、STAT1、LEF1 和 IRF4。使用另外两个独立的软件，还估计了所确定的主调控因子的 TF 活性。通过比较其差异表达的靶基因与来自分子特征数据库（MSigDB）的标志性分子特征，确定的 TFs 有助于炎症、增殖和凋亡的调节。我们的研究结果表明，TF 的影响可用于识别表型特征的潜在主调控因子，并为实验验证提供新的、可成药的靶标。
