Abdulai-Saiku Samira, Gupta Shweta, Wang Dan, Marino Francesca, Moreno Arturo J, Huang Yu, Srivastava Deepak, Panning Barbara, Dubal Dena B
Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Neurosciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
Nature. 2025 Feb;638(8049):152-159. doi: 10.1038/s41586-024-08457-y. Epub 2025 Jan 22.
Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated. This renders either the maternal X (X) chromosome or the paternal X (X) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active. Parent-of-X origin can modify epigenetics through DNA methylation 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 chromosome influences the brain and body-and then delineated unique features of X neurons and X neurons. An active X chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X-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 chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X-imprinted genes improved cognition in ageing female mice. Thus, the X chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X 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.
雌性哺乳动物细胞有两条X染色体，一条来自母方，一条来自父方。在发育过程中，其中一条X染色体会随机失活。这会使母源X染色体（Xm）或父源X染色体（Xp）失活，导致雌性个体之间存在X染色体嵌合现象，有些个体的活跃X染色体存在相当程度或完全的偏斜。X染色体的来源可以通过DNA甲基化以及可能的基因表达来改变表观遗传学；因此，嵌合现象可能缓冲衰老和疾病中失调的过程。然而，X染色体偏斜或其嵌合现象是否会改变雌性个体的功能，目前 largely unknown。在这里，我们测试了活跃X染色体的偏斜是否会影响大脑和身体，然后描绘了Xm神经元和Xp神经元的独特特征。活跃的X染色体在雌性小鼠的整个生命周期中损害认知能力，并随着年龄的增长导致认知能力恶化。认知缺陷伴随着雌性小鼠海马体（学习和记忆的关键中心）中X介导的生物学或表观遗传衰老加速。海马神经元的X染色体上有几个基因被印记，表明认知位点沉默。CRISPR介导的X印记基因激活改善了衰老雌性小鼠的认知能力。因此，X染色体损害认知、加速大脑衰老并使有助于衰老认知的基因沉默。了解X染色体如何损害大脑功能可能有助于更好地理解雌性个体认知健康的异质性，以及有助于预防认知缺陷和大脑衰老的X染色体衍生途径。
