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MOLs are heterogeneous and can transition to immune-like states in MS. However, the dynamics of this process remain unclear. Here, we used single-cell multiome assay for transposase-accessible chromatin and RNA sequencing targeting oligodendroglia (OLG) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at multiple disease stages. We found that immune OLG states appear at early disease stages and persist to late stages, which can be consistent with epigenetic memory of previous neuroinflammation. Transcription factor activity suggested immunosuppression in OLG at early disease stages. Different MOLs exhibit differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5\/MOL6, and showed divergent responses at the epigenetic level during disease evolution. Our single-cell multiomic resource highlights dynamic and subtype-specific responses of OLG to EAE, which might be amenable to modulation in MS.<\/jats:p>","DOI":"10.1038\/s41593-025-02100-3","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T10:02:53Z","timestamp":1763373773000},"page":"2612-2627","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis"],"prefix":"10.1038","volume":"28","author":[{"given":"Chao","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2610-8365","authenticated-orcid":false,"given":"Bastien","family":"Herv\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Meijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie Ann","family":"Rubio Rodr\u00edguez-Kirby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-2823","authenticated-orcid":false,"given":"Andr\u00e9 Ortlieb","family":"Guerreiro Cacais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1228-5923","authenticated-orcid":false,"given":"Petra","family":"Kukanja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukund","family":"Kabbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3756-3354","authenticated-orcid":false,"given":"Tony","family":"Jimenez-Beristain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5012-0305","authenticated-orcid":false,"given":"Eneritz","family":"Agirre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2247-9393","authenticated-orcid":false,"given":"Gon\u00e7alo","family":"Castelo-Branco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"2100_CR1","doi-asserted-by":"publisher","first-page":"itc81","DOI":"10.7326\/AITC202106150","volume":"174","author":"MJ Olek","year":"2021","unstructured":"Olek, M. 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