X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male Brain.
X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male Brain.
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X 染色体因子 Kdm6a 增强认知能力，独立于其在衰老 XY 男性大脑中的去甲基化酶功能。
DOI：
10.1093/gerona/glad007
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dubal,DenaB
中科院分区：
文献类型：
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作者：
Shaw,CayceK;Abdulai-Saiku,Samira;Marino,Francesca;Wang,Dan;Davis,EmilyJ;Panning,Barbara;Dubal,DenaB
在没有痴呆症的老年人群中，男性表现出较短的寿命和更多的认知缺陷。在哺乳动物中，X染色体富含神经基因，是生物性别差异的主要来源，部分原因是雄性显示选择X因子（XY）的表达减少。由于女性的X染色体失活，每个性别（XX和XY）都有一个活跃的X，而一些基因，如Kdm 6a，在女性中转录逃避沉默，导致男性的转录水平较低。Kdm 6a是已知的组蛋白去甲基化酶（H3 K27 me 2/3），具有与突触可塑性和认知相关的多个功能结构域。升高Kdm 6是否有益于老年男性大脑，以及这是否需要其去甲基化酶功能仍然未知。我们使用慢病毒介导的X因子在老龄雄性小鼠海马中的过表达，并在Morris水迷宫中测试它们的认知和行为。我们发现，Kdm 6a的急剧增加--以一种没有去甲基酶功能的形式--选择性地改善了衰老XY大脑的学习和记忆，而不改变总的活动或焦虑样指标。进一步了解Kdm 6a的脱甲基酶非依赖性下游机制可能会导致治疗两性年龄诱导的认知缺陷的新疗法。
Males exhibit shorter life span and more cognitive deficits, in the absence of dementia, in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors (XY). While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such asKdm6a, transcriptionally escape silencing in females—resulting in lower transcript levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevatingKdm6acould benefit the aged male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water-maze. We found that acutely increasingKdm6a—in a form without demethylase function—selectively improved learning and memory, in the aging XY brain, without altering total activity or anxiety-like measures. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.