The Chromatin Accessibility Landscape of Peripheral Blood Mononuclear Cells in Patients With Systemic Lupus Erythematosus at Single-Cell Resolution

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.

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“…AR suppresses IL-12A expression lowering the efficacy of NK cell cytotoxicity ( 126 ). NR2C2 is an integrant of an axis identified to promote abnormal T cell activity on lupus ( 131 ). Our results suggest a complex responsive state in NK cells predominantly orientated to an antiviral response.…”

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“…TBX4 is ubiquitously expressed in several tissues and is crucial for organogenesis, especially in proper lung organogenesis ( 60 ). Moreover, TBX4 play a key role in systemic lupus erythematosus (SLE) disease pathogenesis through mediating abnormal T cell activity ( 61 ). In mouse models, specific knockout of TBX4 or perturbation of TBX4 gene function in fibroblasts markedly relieved lung fibrosis after bleomycin-induced damage ( 59 ).…”

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“…However, the proportion of T cells was significantly reduced compared with an increase of monocytes, B cells, dendritic cells (DCs), and granulocytes [ 53 ]. A subtype of T cells, proliferating T cells in massive numbers with few marker genes, had been found in PBMCs by scATAC-seq, which are only found in PBMCs of SLE recently, and may be involved in the middle/late cell cycle transition, indicating that SLE has high proliferative activity and differentiation state of T cells [ 54 ]. Therefore, genes that contribute to T cell activity may be essential factors that drive T cell proliferation and lead to abnormal immune responses in SLE patients.…”

“…In addition to activated T cells proliferation, B cells dysregulation and disruption of tolerance and production of pathogenic autoantibodies are also more important in the pathogenesis of SLE [ 54 ]. ScRNA-seq revealed that ISGs in expanded B cells, especially double negative switch memory cell B cell subtype and plasma cells, were also upregulated in SLE PBMCs [ 55 ].…”

“…Moreover, ISGs up-regulation in PBMCs was mainly due to the significant response of B cells to IFN [ 58 , 59 ]. B cells may be involved in the regulation of RNA splicing and apoptotic signaling pathway, transcription initiation from RNA polymerase II promoter, and T cells activation, respectively, in SLE [ 54 ]. B cells phenotype has continuity across the original and activated B cells, with few cells in the intermediate state between plasma cells and the original or activated B cells, and the lack of differentiation into plasma cells in inflammatory kidneys [ 6 , 55 ].…”