Mapping the cell-type-specific molecular and genetic basis of lupus using single cell multiomics

Abstract Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestries. SLE patients present a broad range of symptoms across multiple organ systems and differentially respond to treatments. Our central hypothesis is twofold: 1) genetic drivers of SLE affect gene regulatory mechanisms in specific cell types and activation states, and 2) cellular drivers responsible for disease initiation and exacerbation may exhibit transcriptional regulatory states (e.g., epigenomic states) poised to respond to environmental disease triggers. To test this hypothesis, we will use highly innovative multiplexed multimodal single-cell sequencing to map cell-type-specific epigenomic, transcriptomic, and surface protein features that stratify patients. When integrated with SLE GWAS data, we will further fine-map SLE-associated variants and annotate the cellular contexts by which associated variants act through. Finally, utilizing a novel strategy to sequence capillary blood, we will characterize circulating immune cells in SLE patients during flare, resolution, and response to discrete treatments. 3