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In this study, we dissected the contribution of DNA methylation to the regulation of <jats:italic>ATXN1<\/jats:italic> in multiple sclerosis (MS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We interrogated a DNA methylation dataset previously generated via bisulfate DNA sequencing (BS\u2010seq) in sorted peripheral immune cytotypes (CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells, CD19<jats:sup>+<\/jats:sup> B cells, and CD14<jats:sup>+<\/jats:sup> monocytes) isolated from untreated MS patients at symptoms onset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we report that <jats:italic>ATXN1<\/jats:italic> undergoes hypo\u2010methylation at four distinct regions upon MS, exclusively in B cells. We also highlight how these differentially methylated sites overlap with other regulatory epigenetic marks and MS risk variants. Lastly, we employ luciferase assays to assess the functionality of these regions, showing that the loss of methylation leads to an increase in <jats:italic>ATXN1<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Altogether, these findings provide biological insights into ataxin\u20101 regulation in the immune system as well as into the molecular mechanisms underlying MS risk.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51618","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T06:41:20Z","timestamp":1659076880000},"page":"1186-1194","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Epigenetic control of ataxin\u20101 in multiple sclerosis"],"prefix":"10.1002","volume":"9","author":[{"given":"Qin","family":"Ma","sequence":"first","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology University of California  San Francisco California 94158 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge R.","family":"Oksenberg","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology University of California  San Francisco California 94158 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7510-9658","authenticated-orcid":false,"given":"Alessandro","family":"Didonna","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology University of California  San Francisco California 94158 USA"},{"name":"Department of Anatomy and Cell Biology East Carolina University  Greenville North Carolina 27834 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