Abstract
ObjectiveSystemic lupus erythematosus (SLE) is a complex autoimmune disease, and various immune cells are involved in the initiation, progression, and regulation of SLE. Our goal was to reveal the chromatin accessibility landscape of peripheral blood mononuclear cells (PBMCs) in SLE patients at single-cell resolution and identify the transcription factors (TFs) that may drive abnormal immune responses.MethodsThe assay for transposase accessible chromatin in single-cell sequencing (scATAC-seq) method was applied to map the landscape of active regulatory DNA in immune cells from SLE patients at single-cell resolution, followed by clustering, peak annotation and motif analysis of PBMCs in SLE.ResultsPeripheral blood mononuclear cells were robustly clustered based on their types without using antibodies. We identified twenty patterns of TF activation that drive abnormal immune responses in SLE patients. Then, we observed ten genes that were highly associated with SLE pathogenesis by altering T cell activity. Finally, we found 12 key TFs regulating the above six genes (CD83, ELF4, ITPKB, RAB27A, RUNX3, and ZMIZ1) that may be related to SLE disease pathogenesis and were significantly enriched in SLE patients (p <0.05, FC >2). With qPCR experiments on CD83, ELF4, RUNX3, and ZMIZ1 in B cells, we observed a significant difference in the expression of genes (ELF4, RUNX3, and ZMIZ1), which were regulated by seven TFs (EWSR1-FLI1, MAF, MAFA, NFIB, NR2C2 (var. 2), TBX4, and TBX5). Meanwhile, the seven TFs showed highly accessible binding sites in SLE patients.ConclusionsThese results confirm the importance of using single-cell sequencing to uncover the real features of immune cells in SLE patients, reveal key TFs in SLE-PBMCs, and provide foundational insights relevant for epigenetic therapy.
Highlights
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects every organ and system in the body
Since we used a fresh sample for higher data quality, our study focuses on the general landscapes of immune cells instead of cell heterogeneity in SLE patients
When calculating the cell ratios in both the PBMC_SLE and PBMC_NC groups, we found a significant difference in T cells and B cells (Student’s t-test, p
Summary
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects every organ and system in the body. The loss of tolerance in the immune system results in autoantibody production, immune complex deposition, and complement activation, which lead to systemic inflammation and target tissue damage [1]. Genetic factors are essential in SLE susceptibility, according to family studies and the concordance rate between twins [2]. Gene sequences alone explain only a minority of SLE heritability. Epigenetic marks have emerged as keys to understanding a portion of the missing heritability [3], and noncoding elements within cell-type-specific genomes are vital to understanding SLE pathogenesis [4]. Little is known about the related pathogenesis
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