Transcription Factor Activity Inference in Systemic Lupus Erythematosus.

Raul Lopez-Dominguez,Christian Holland,Daniel Toro-Dominguez,Jordi Martorell-Marugan,Julio Saez-Rodriguez,Marta Alarcon-Riquelme,Daniel Goldman,Pedro Carmona-Saez,Michelle Petri,Adrian Garcia-Moreno

doi:10.3390/life11040299

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Highlights

Systemic Lupus Erythematosus (SLE) is a complex and multisystemic autoimmune disease characterized by the production of autoantibodies leading to chronic inflammation and organ damage
We analyzed the distribution of the other cellular proportions using cibersort, a deconvolution algorithm [21] and differences in other cell types were observed in one of the cohorts, we did not find significant differences across clusters that were consistent in both datasets (See Figure S1). These findings were consistent in both independent datasets, and they were in agreement with our previous observations reported in [10] where we described a stratification of SLE patients into three main groups, mainly associated with differences in the percentages of these cell populations when disease activity increases
The positional analysis of these SLE associated loci has revealed that most of them are located in regulatory regions, but there is a lack of a global analysis of transcription factors (TFs) activity patterns associated with SLE disease

Summary

Introduction

Systemic Lupus Erythematosus (SLE) is a complex and multisystemic autoimmune disease characterized by the production of autoantibodies leading to chronic inflammation and organ damage. SLE is very heterogeneous, with possible affliction in almost any organ and diverse clinical manifestations including skin rashes, arthritis and renal failure [1]. Disease activity can be measured by several indices, but one of the most accepted is the SLE Disease Activity Index (SLEDAI) It is measured by 24 laboratory and weighted clinical variables in nine organ systems including renal, skin and arthritis [3]. 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. 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. Conclusions: 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

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Conclusion