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During development, one X chromosome randomly becomes inactivated\n                    <jats:sup>1\u20134<\/jats:sup>\n                    . This renders either the maternal X (X\n                    <jats:sub>m<\/jats:sub>\n                    ) chromosome or the paternal X (X\n                    <jats:sub>p<\/jats:sub>\n                    ) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active\n                    <jats:sup>5\u20137<\/jats:sup>\n                    . Parent-of-X origin can modify epigenetics through DNA methylation\n                    <jats:sup>8,9<\/jats:sup>\n                    and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active X\n                    <jats:sub>m<\/jats:sub>\n                    chromosome influences the brain and body\u2014and then delineated unique features of X\n                    <jats:sub>m<\/jats:sub>\n                    neurons and X\n                    <jats:sub>p<\/jats:sub>\n                    neurons. An active X\n                    <jats:sub>m<\/jats:sub>\n                    chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X\n                    <jats:sub>m<\/jats:sub>\n                    -mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the X\n                    <jats:sub>m<\/jats:sub>\n                    chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X\n                    <jats:sub>m<\/jats:sub>\n                    -imprinted genes improved cognition in ageing female mice. Thus, the X\n                    <jats:sub>m<\/jats:sub>\n                    chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X\n                    <jats:sub>m<\/jats:sub>\n                    impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08457-y","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T11:07:03Z","timestamp":1737544023000},"page":"152-159","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The maternal X chromosome affects cognition and brain ageing in female mice"],"prefix":"10.1038","volume":"638","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-4646","authenticated-orcid":false,"given":"Samira","family":"Abdulai-Saiku","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shweta","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7899-4282","authenticated-orcid":false,"given":"Francesca","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo J.","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3480-5953","authenticated-orcid":false,"given":"Deepak","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Panning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-4372","authenticated-orcid":false,"given":"Dena B.","family":"Dubal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"8457_CR1","doi-asserted-by":"publisher","first-page":"R242","DOI":"10.1093\/hmg\/ddy148","volume":"27","author":"BP Balaton","year":"2018","unstructured":"Balaton, B. 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