Transcription Factor Activity Inference in Systemic Lupus Erythematosus
Metadata
Show full item recordEditorial
MDPI
Materia
Transcription factor activity inference Cluster analysis Systemic lupus erythematosus Disease classification
Date
2021Referencia bibliográfica
Lopez-Dominguez, R.; Toro-Dominguez, D.; Martorell-Marugan, J.; Garcia-Moreno, A.; Holland, C.H.; Saez-Rodriguez, J.; Goldman, D.; Petri, M.A.; Alarcon-Riquelme, M.E.; Carmona-Saez, P. Transcription Factor Activity Inference in Systemic Lupus Erythematosus. Life 2021, 11, 299. https://doi.org/10.3390/ life11040299
Sponsorship
Innovative Medicines Initiative 2 Joint Undertaking (JU) - 831434 (3TR); European Union’s Horizon 2020 research and innovation program and EFPIA; NIH AR69572 and NIH RO-1 grant AR069572Abstract
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.