The maternal X chromosome affects cognition and brain ageing in female mice

Samira Abdulai-Saiku, Shweta Gupta, Dan Wang, Francesca Marino, Arturo J. Moreno, Yu Huang, Deepak Srivastava, Barbara Panning and Dena B. Dubal ()
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Samira Abdulai-Saiku: University of California San Francisco
Shweta Gupta: University of California San Francisco
Dan Wang: University of California San Francisco
Francesca Marino: University of California San Francisco
Arturo J. Moreno: University of California San Francisco
Yu Huang: Gladstone Institute of Cardiovascular Disease
Deepak Srivastava: Gladstone Institute of Cardiovascular Disease
Barbara Panning: University of California San Francisco
Dena B. Dubal: University of California San Francisco

Nature, 2025, vol. 638, issue 8049, 152-159

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 inactivated1–4. This renders either the maternal X (Xm) chromosome or the paternal X (Xp) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active5–7. Parent-of-X origin can modify epigenetics through DNA methylation8,9 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 Xm chromosome influences the brain and body—and then delineated unique features of Xm neurons and Xp neurons. An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm-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 Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of Xm-imprinted genes improved cognition in ageing female mice. Thus, the Xm chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how Xm 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.

Date: 2025
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DOI: 10.1038/s41586-024-08457-y

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