GSE137143
Cell-Type-Specific Transcriptome of CD4+, CD8+ T cells and CD14+ monocytes in multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system in which both genetic and environmental factors are thought to be involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbor genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in MS are not well understood. To assess cell-type-specific gene expression in a large cohort of MS patients, we sequenced the whole transcriptome of sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive MS patients (n=122) and healthy subjects (n=22). Next, we performed a comprehensive analysis of the RNA sequencing dataset and identified 612 differentially expressed genes (DEGs) in CD14+ monocytes, 464 in CD4+ T cells, and 93 in CD8+ T cells. Notably, about one third (36.6%) of DEGs were non-coding RNAs, the majority of which (88.2%) were down-regulated in MS. We identified large co-expressed gene modules and cis-eQTLs with key MS genes in each cell subset. Importantly, we discovered dysregulation of NAE1, a subunit of NEDD8 activating enzyme (NAE), in CD4+ T cells which activates the neddylation pathway. Finally, we demonstrated that NAE inhibition using Pevonedistat (MLN4924) dampened disease severity in murine experimental autoimmune encephalomyelitis (EAE). Our findings provide novel insights into MS-associated gene regulation unraveling neddylation as a crucial pathway in MS pathogenesis with implications for the development of tailored disease-modifying agents. Overall design: Whole transcriptome profile of sorted CD4+ T cells, CD8+ T cells, and CD14+ monocytes in treatment naïve MS patients (n=122) and healthy controls (n=22)