Transcription Factor Activity Inference in Systemic Lupus Erythematosus

Life, vol. 11, pp. 299

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.

Authors 10

1. Raúl López-Domínguez

   Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

   Affiliation as printed

   Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

2. Daniel Toro Dominguez

   Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

   Affiliation as printed

   Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

3. Jordi Martorell‐Marugán

   Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

   Affiliation as printed

   Atrys Health S.A., 08025 Barcelona, Spain

   Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

4. Adrián García-Moreno

   Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

   Affiliation as printed

   Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

5. Christian H. Holland Aachen Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine

   Heidelberg University · RWTH Aachen University

   Affiliation as printed

   Faculty of Medicine, Institute of Computational Biomedicine, Heidelberg University, 69120 Heidelberg, Germany

   Joint Research Center for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52062 Aachen, Germany

6. Julio Sáez-Rodríguez Aachen Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine

   Heidelberg University · RWTH Aachen University

   Affiliation as printed

   Faculty of Medicine, Institute of Computational Biomedicine, Heidelberg University, 69120 Heidelberg, Germany

   Joint Research Center for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52062 Aachen, Germany

7. DANIEL W. GOLDMAN

   Johns Hopkins University · Johns Hopkins Medicine

   Affiliation as printed

   Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

8. Petri Michelle

   Johns Hopkins University · Johns Hopkins Medicine

   Affiliation as printed

   Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

9. Marta Eugenia Alarcón-Riquelme corresponding

   Universidad de Granada · Karolinska Institutet · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

   Affiliation as printed

   Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

   Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, 17177 Solna, Sweden

10. Pedro Carmona‐Sáez corresponding Aachen Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine

    Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research · RWTH Aachen University

    Affiliation as printed

    Biostatistics, Department of Statistics, Faculty of Medicine, University of Granada, 18071 Granada, Spain

    Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain

    Joint Research Center for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52062 Aachen, Germany