Integrative analysis of transcriptional regulation unveils regulatory modules that stratify lupus transcriptome

Abstract

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with complex pathogenesis and high clinical heterogeneity. On the one hand, recent advances in genome-wide association studies (GWAS) have markedly improved our understanding of the genetic architecture of SLE, identifying more than 80 susceptibility loci associated with the disease. On the other hand, the identified variants so far only explain approximately 20% of disease heritability for SLE and the detailed disease mechanisms remain elusive. Furthermore, more than a decade of monitoring of the SLE transcriptome provided a plethora of supports on the important role of interferon (IFN) signature gene expression in the etiology of the disease. However, the specific contribution of different interferon stimulated genes (ISGs) to the IFN signature and to SLE pathogenesis is not yet resolved. Fortunately, high-throughput technologies have revolutionized medical research and prompted the generation of massive multi-omics data, and integrative analysis of them may help us better explicate the complicated disease mechanisms. In this dissertation, making use of transcriptomic data on SLE, we identified 750 differentially expressed genes (DEGs) in T, B lymphocytes and peripheral blood cells. By exhaustive usage of transcription factor (TF) ChIP-seq data from The Encyclopedia of DNA Elements (ENCODE) project, we analyzed TFs bound to the regulatory regions of the upregulated DEGs and identified enriched TFs that play vital roles in SLE pathogenesis. Based on the TF binding profiles for upregulated DEGs, an SLE co-regulatory network was constructed. Intriguingly, further partitioning of this inferential network unveiled multiple co-regulatory modules among upregulated DEGs. The modular regulatory repertoire not only stratifies IFN signature but dissects SLE pathogenesis, including complement cascade, cell cycle regulation, NETosis, Polycomb Repressive Complex 2 (PRC2) epigenetic regulation, phenotypic manifestation and necroptosis modules. To decipher the functional relationships between genetic findings and gene expression changes, we also identified a hierarchical regulatory system with TFs regulated by disease-associated genes (DAGs) and in turn modulating gene expression by incorporating protein-protein interaction (PPI) information. Additionally, we proposed promising candidate targets for novel drug discovery, potentially helping SLE patients in the clinic. Overall, the strategy we used in multi-omics data analysis provided an efficient and powerful way for interpretation of large-scale datasets, and the findings in these analyses expanded our understanding of gene expression regulation and its roles in SLE pathogenesis.