Senior Scientist Abbvie Malden, Massachusetts, United States
Abstract Text: Autoimmune disorders such as systemic lupus erythematosus (SLE), result from a complex interaction of genetic and environmental factors. Understanding cell type-specific epigenetic processes and how they interact with genetics remains a critical yet underexplored area. In the current project, we generated the largest single-cell chromatin accessibility profile of human peripheral blood mononuclear cells (PBMC) of any autoimmune disease to date to interrogate genetic-epigenetic interactions in cell type-specific manner. We generated over 1.1 million single-cell chromatin accessibility (scATACseq) profiles using PBMCs from a cohort of 70 SLE patients and healthy controls from two ethnic groups. We identified subsets of Bcell memory, and CD8+ effector memory T cells were expanded in SLE. We performed differential peak accessibility analysis within each major PBMC cell type and identified 9,104 differentially accessible peaks across PBMC cell types in known and novel genes including cytokine signaling and receptors such as CXCR4 and IL7R, integrin family such as ITGB2, ITGAM (CD11b), CORO1A. Transcription factor motif enrichment analysis defines key transcription factor regulators in SLE across PBMC cell types including AP-1 factors FOS, JUN, BACH in lymphocytes and CEBP family in monocytes modulating critical gene networks. Incorporation of genotyping enabled Chromatin accessibility quantitative trait loci (caQTL) analysis identifies causal SLE GWAS risk variants regulating accessibility at key genes including SLC15A4 and OVOL1. This research provides novel insights into the genetic and epigenetic transcription factor gene regulation of SLE in pathogenic immune cell types. These findings offer a new depth of understanding in SLE pathogenesis and potential therapeutic targets.
