美国加州大学旧金山分校Dena B. Dubal小组发现，母源X染色体影响雌性小鼠的认知和大脑衰老。2025年1月22日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员测试了偏向活性母源X（X_m）染色体是否影响大脑和身体——并进一步描绘了X_m神经元和父源X（X_p）神经元的独特特征。活性X_m染色体在雌性小鼠的整个生命周期中损害了认知，并且随着年龄的增长，认知能力进一步恶化。认知缺陷伴随X_m介导的生物学或表观遗传学加速衰老，特别是在学习和记忆的关键区域——海马。若干基因在海马神经元的X_m染色体上表现为印记，提示有认知相关的位点被沉默。通过CRISPR介导的X_m印记基因激活改善了衰老雌性小鼠的认知能力。

因此，X_m染色体损害了认知、加速了大脑衰老，并沉默了在衰老过程中影响认知的基因。理解X_m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，并为发现有助于预防认知缺陷和大脑衰老的X染色体衍生通路提供线索。

据悉，雌性哺乳动物细胞有两个X染色体，一个来自母方，一个来自父方。在发育过程中，一个X染色体会随机失活。这导致X_m染色体或X_p染色体失活，形成X嵌合体。不同雌性个体之间的X染色体失活模式存在差异，一些个体表现出明显或完全偏向某一X染色体的活性。X染色体的父源或母源来源可能通过DNA甲基化和可能的基因表达改变表观遗传学；因此，X嵌合体可能对衰老和疾病中的失调过程起到缓冲作用。然而，X偏向或其嵌合体是否改变雌性个体的功能仍然不清楚。

附：英文原文

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

Author: Abdulai-Saiku, Samira, Gupta, Shweta, Wang, Dan, Marino, Francesca, Moreno, Arturo J., Huang, Yu, Srivastava, Deepak, Panning, Barbara, Dubal, Dena B.

Issue&Volume: 2025-01-22

Abstract: Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated1,2,3,4. 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 active5,6,7. 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.

DOI: 10.1038/s41586-024-08457-y

Source: https://www.nature.com/articles/s41586-024-08457-y