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bioRxiv · 10.1101/2022.03.09.483691

The maternal X chromosome impairs cognition and accelerates brain aging through epigenetic modulation in female mice

Abdulai-Saiku, S.·Gupta, S.·Wang, D.·Moreno, A.·Huang, Y.·Srivastava, D.·Panning, B.·Dubal, D.
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Abstract

Female mammalian cells harbor two X chromosomes, one of maternal and one of paternal origin. During development, one X randomly inactivates1-4. This renders either the maternal or paternal X active, causing X mosaicism that varies among individual females, with some showing considerable or complete skew in the general female population5-7. Parent-of-X-origin can modify epigenetics via DNA methylation8, 9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in aging and disease. However, whether X skewing - or its mosaicism - alters functions in females is largely unknown. Here we tested whether skew toward the maternal X (Xm) influences key functions of the body. Among cardiac, bone, metabolic, and brain functions, Xm selectively impaired cognition in female mice throughout the lifespan. Cognitive deficits were accompanied by Xm-mediated acceleration of biologic or epigenetic aging of the female hippocampus, a key center for learning and memory. Xm showed epigenetic imprinting of several genes within hippocampal neurons, suggesting silenced cognitive loci. Thus, the maternal X chromosome impaired cognition, accelerated brain aging, and silenced genes. Understanding how the maternal X impairs brain function could lead to new understanding of female heterogeneity in cognitive heath and to X chromosome-derived pathways against cognitive deficits and brain aging.

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Abdulai-Saiku, S., Gupta, S., Wang, D., Moreno, A., Huang, Y., Srivastava, D., Panning, B., Dubal, D.. 2022-03-12. The maternal X chromosome impairs cognition and accelerates brain aging through epigenetic modulation in female mice. https://doi.org/10.1101/2022.03.09.483691

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