{"doi":"10.1038/s41586-024-08457-y","title":"The maternal X chromosome affects cognition and brain ageing in female mice","abstract":"Abstract Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated 1–4 . This renders either the maternal X (X m ) chromosome or the paternal X (X p ) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active 5–7 . Parent-of-X origin can modify epigenetics through DNA methylation 8,9 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 m chromosome influences the brain and body—and then delineated unique features of X m neurons and X p neurons. An active X m chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X m -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 m chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X m -imprinted genes improved cognition in ageing female mice. Thus, the X m chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X m 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.","journal":"Nature","year":2025,"id":510936,"datarank":0.8044253560486545,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.37086959236422984,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.37086959236422984,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":13,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE200461"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890673,"name":"Shweta Gupta","orcid":"0000-0002-5900-4108","position":1,"is_corresponding":false},{"id":1056095,"name":"Dan Wang","orcid":"0000-0002-4298-1412","position":2,"is_corresponding":false},{"id":825020,"name":"Francesca Marino","orcid":"0000-0002-7899-4282","position":3,"is_corresponding":false},{"id":250324,"name":"Arturo J. Moreno","orcid":"0000-0003-2357-5854","position":4,"is_corresponding":false},{"id":605728,"name":"Yu Huang","orcid":"0000-0003-2560-5674","position":5,"is_corresponding":false},{"id":251046,"name":"Deepak Srivastava","orcid":"0000-0002-3480-5953","position":6,"is_corresponding":false},{"id":250332,"name":"Barbara Panning","orcid":"0000-0002-8301-1172","position":7,"is_corresponding":false},{"id":250335,"name":"Dena B. Dubal","orcid":"0000-0001-7504-4372","position":8,"is_corresponding":false},{"id":250320,"name":"Samira Abdulai-Saiku","orcid":"0000-0003-3772-4646","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"39843739","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}