Lopez-Dominguez Raul, Toro-Dominguez Daniel, Martorell-Marugan Jordi, Garcia-Moreno Adrian, Holland Christian H, Saez-Rodriguez Julio, Goldman Daniel, Petri Michelle A, Alarcon-Riquelme Marta E, Carmona-Saez Pedro
Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain.
Atrys Health S.A., 08025 Barcelona, Spain.
Life (Basel). 2021 Apr 1;11(4):299. doi: 10.3390/life11040299.
Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE.
In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples.
TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets-one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE.
These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.
系统性红斑狼疮（SLE）是一种临床表现多样的全身性自身免疫性疾病。尽管大多数与SLE相关的基因座位于调控区域，但缺乏关于转录因子（TFs）活性、TFs调控模式或细胞或样本特异性调控回路的全面信息。这项工作的目的是破译与SLE相关的TFs。
为了解析SLE的调控机制，我们从几乎所有人类TFs的转录组数据中推断TF活性，根据估计的TF活性定义SLE患者群体，并分析了两个不同队列中SLE患者与健康样本之间的差异活性模式。转录因子活性矩阵用于对SLE患者进行分层，并定义疾病样本与对照样本之间具有统计学显著差异活性的TFs集合。
TF活性能够识别出以不同的中性粒细胞与淋巴细胞比率（NLR）为特征的两个主要患者亚组，在两个独立的数据集中具有一致的模式——一个来自儿科患者，另一个来自成人。此外，在对比所有患者亚组和对照组后，我们获得了一份由14个TFs组成的重要且可靠的清单，这些TFs通过不同的机制和途径参与了SLE的失调。其中，发现了SLE的知名调节因子，如STAT或IRF，但其他因子提示了可能在SLE中起重要作用的新途径。
这些结果为理解SLE潜在的调控机制以及SLE异质性背后已确定的调控因子提供了基础，这些调控因子可能是潜在的治疗靶点。
