Multiomics Profiling During Autoimmune Demyelination Highlights a Complex Regulatory Role for Ataxin-1 in B Cells

Recent evidence from genome-wide association studies has linked the ataxin-1 gene (ATXN1) to an increased risk of developing the autoimmune demyelinating disorder multiple sclerosis. From a mechanistic standpoint, our previous work explained this genetic association by defining an immunomodulatory function for ataxin-1 in controlling specific genetic programs underlying B cell proliferation, activation, immunoglobulin production, and antigen presentation. Here, we employed a high-resolution multiomics analytical pipeline to further dissect the role of ataxin-1 in distinct B cell subsets upon encephalitogenic stress. By combining single-nuclei RNA-seq and ATAC-seq, along with mass-spectrometry proteomics, we documented that ataxin-1 is significantly enriched in B1 cells, marginal zone B cells, memory B cells, and precursor B cells. Pathway analysis highlighted that ataxin-1 is implicated in RNA splicing and translation processes. Conversely, no major effects were implicated for ataxin-1 in chromatin remodeling in the B cell population. Our findings expand the current knowledge of the cellular functions controlled by ataxin-1 outside of the central nervous system, and further describe a key regulator of B cell biology in health and disease.