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

ABSTRACT

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.