GSE183970
Gene-regulatory network study of rheumatoid arthritis in single-cell chromatin landscapes of peripheral blood mononuclear cells
Rheumatoid arthritis is a chronic autoinflammatory disease with an elusive etiology. Assays for transposase-accessible chromatin with single-cell sequencing (scATAC-seq) contribute to the progress in epigenetic studies. However, the impact of epigenetic technology on autoimmune diseases has not been objectively analyzed. Therefore, scATAC-seq was performed to generate a high-resolution map of accessible loci in peripheral blood mononuclear cells (PBMCs) of RA patients at the single-cell level. The purpose of our project was to discover the transcription factors (TFs) that were involved in the pathogenesis of RA at single-cell resolution. In our research, we obtained 22 accessible chromatin patterns. Then, 10 key TFs were involved in the RA pathogenesis by regulating the activity of MAP kinase. Consequently, two genes (PTPRC, SPAG9) regulated by 10 key TFs were found that may be associated with RA disease pathogenesis and these TFs were obviously enriched in RA patients (p<0.05, FC>1.2). With further qPCR validation on PTPRC and SPAG9 in monocytes, we found differential expression of these two genes, which were regulated by eight TFs (ZNF384, HNF1B, DMRTA2, MEF2A, NFE2L1, CREB3L4 (var. 2), FOSL2::JUNB (var. 2), MEF2B). What is more, the eight TFs showed highly accessible binding sites in RA patients. These findings demonstrate the value of using scATAC-seq to reveal transcriptional regulatory variation in RA-derived PBMCs, providing insights on therapy from an epigenetic perspective. Overall design: Rheumatoid arthritis (RA) is a chronic auto-inflammatory disease with significant unknown etiology. Assay for transposase accessible chromatin in single cells sequencing (scATAC-seq) is related to great progress in epigenetic study, including cancer biology. However, the impact of this technology on autoimmune disease has not been objectively analyzed. Hence, scATAC-seq was performed to profile a high-resolution map of accessible loci in RA at a single-cell level. We identified five major clusters using cell type-specific marker genes and further obtained 22 patterns of transcription factor (TF) among them. Consequently, our findings revealed five genes associated with RA pathogenesis in the T cell activity pathway and 43 remarkable enriched TF motifs in RA patients. Also, Dendritic cells and Natural killer cells showed abnormal signals in the virus infection-related pathways. These findings could provide insights into epigenetic therapy in the future.