{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:58:07Z","timestamp":1793732287777,"version":"4.6.1"},"reference-count":94,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"820","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,10,15]]},"abstract":"<jats:p>\n            Women are more susceptible to multiple sclerosis (MS) than men, with a reported incidence ratio of ~3:1.\n            <jats:italic toggle=\"yes\">Kdm6a<\/jats:italic>\n            is an X-chromosomal gene that escapes X inactivation, leading to higher expression of the histone demethylase KDM6A in females compared with males. Here, we focused on the role of\n            <jats:italic toggle=\"yes\">Kdm6a<\/jats:italic>\n            in microglia in MS because this cell type plays a key role in the neuropathology of MS.\n            <jats:italic toggle=\"yes\">Kdm6a<\/jats:italic>\n            was selectively deleted from microglia in experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. Deletion of\n            <jats:italic toggle=\"yes\">Kdm6a<\/jats:italic>\n            in microglia ameliorated pathology, reduced the expression of disease-associated markers, increased the expression of resting microglial markers, and reversed other translatome changes in spinal cord tissues of female EAE mice. Deletion of\n            <jats:italic toggle=\"yes\">Kdm6a<\/jats:italic>\n            in microglia had only very minor effects on EAE in male mice. The diabetes medicine metformin, which also blocks KDM6A\u2019s histone demethylase activity, ameliorated EAE in females, but not males, and normalized translatome profiles in microglia. CUT&amp;RUN and sequencing analysis of microglial nuclei identified genes bound by KDM6A. When combined with translatomic analysis, this revealed correspondence between KDM6A protein binding and gene expression changes. Transcriptomic analysis of human microglia confirmed the higher expression of\n            <jats:italic toggle=\"yes\">KDM6A<\/jats:italic>\n            in women compared with men and revealed that more microglial genes were dysregulated in women than in men with MS. Our results suggest that\n            <jats:italic toggle=\"yes\">KDM6A<\/jats:italic>\n            might contribute to sex differences in susceptibility to MS.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adq3401","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:58:27Z","timestamp":1760551107000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Deletion of the X-chromosomal gene\n            <i>Kdm6a<\/i>\n            in microglia of female mice ameliorates neuroinflammation and restores translatome profiles"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-0174","authenticated-orcid":true,"given":"Yuichiro","family":"Itoh","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, 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Los Angeles, CA 90095, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2620-4346","authenticated-orcid":true,"given":"Rhonda R.","family":"Voskuhl","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, 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