Identification of Regulatory Modules That Stratify Lupus Disease Mechanism through Integrating Multi-Omics Data

Abstract

Although recent advances in genetic studies have shed light on systemic lupus erythematosus (SLE), its detailed mechanisms remain elusive. In this study, using datasets on SLE transcriptomic profiles, we identified 750 differentially expressed genes (DEGs) in T and B lymphocytes and peripheral blood cells. Using transcription factor (TF) binding data derived from chromatin immunoprecipitation sequencing (ChIP-seq) experiments from the Encyclopedia of DNA Elements (ENCODE) project, we inferred networks of co-regulated genes (NcRGs) based on binding profiles of the upregulated DEGs by significantly enriched TFs. Modularization analysis of NcRGs identified co-regulatory modules among the DEGs and master TFs vital for each module. Remarkably, the co-regulatory modules stratified the common SLE interferon (IFN) signature and revealed SLE pathogenesis pathways, including the complement cascade, cell cycle regulation, NETosis, and epigenetic regulation. By integrative analyses of disease-associated genes (DAGs), DEGs, and enriched TFs, as well as proteins interacting with them, we identified a hierarchical regulatory cascade with TFs regulated by DAGs, which in turn regulates gene expression. Integrative analysis of multi-omics data provided valuable molecular insights into the molecular mechanisms of SLE.