Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease which targets mature oligodendrocytes (MOLs) and their myelin. MOLs are transcriptionally heterogeneous, and can transition to immune-like states in the context of MS. However, the intricacies of their dynamics throughout disease progression remain poorly understood. Here, we employed simultaneous single-cell multiome ATAC and RNA sequencing targeting oligodendroglia (OLGs) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model, at different stages of the disease course. We found that the transition to immune OLGs states occurs already at early stages of EAE and these persist at late stages of the disease, consistent with epigenetic memory of previous neuroinflammation. Interestingly, transcription factor activity suggested immunosuppression activity in MOLs at early stages of EAE and we also observed a transitory activation of a regenerative programme in MOLs at this stage. Importantly, different MOLs present a differential responsiveness to EAE, with MOL2 exhibiting stronger transcriptional immune response than MOL5/6. Moreover, we observed divergence responses at the epigenetic level of MOL2 and MOL5/6 during disease evolution. Thus, our single-cell multiomic resource highlights dynamic and distinct responses of OLG subpopulations to the evolving environment in EAE, which might modulate their response to regenerative therapeutic interventions in MS. Overall design: Sox10:Cre-RCE:LoxP mice are a strain of mice obtained originally by crossing mice with Cre recombinase under the control of the Sox10 promoter with reporter mice RCE:loxP-EGFP to label the complete oligodendrocyte (OL) lineage